DK151024B - METHOD FOR PREPARING 6- (D-ALFA-AMINO- (P-HYDROXYPHENYL) ACETIMIDO) -PENICILLANIC ACID - Google Patents
METHOD FOR PREPARING 6- (D-ALFA-AMINO- (P-HYDROXYPHENYL) ACETIMIDO) -PENICILLANIC ACID Download PDFInfo
- Publication number
- DK151024B DK151024B DK391478AA DK391478A DK151024B DK 151024 B DK151024 B DK 151024B DK 391478A A DK391478A A DK 391478AA DK 391478 A DK391478 A DK 391478A DK 151024 B DK151024 B DK 151024B
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- Prior art keywords
- solvent
- acid
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- Prior art date
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- 238000000034 method Methods 0.000 title claims description 47
- -1 ACETIMIDO Chemical class 0.000 title claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 90
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims description 38
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 38
- 150000008064 anhydrides Chemical class 0.000 claims description 37
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims description 36
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 30
- 230000008569 process Effects 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000005917 acylation reaction Methods 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 20
- 239000011541 reaction mixture Substances 0.000 claims description 20
- 230000010933 acylation Effects 0.000 claims description 19
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 14
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 13
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 13
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 13
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 239000011591 potassium Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000006184 cosolvent Substances 0.000 claims description 10
- 150000003512 tertiary amines Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- QMWWAEFYIXXXQW-UHFFFAOYSA-M potassium;2-[(4-ethoxy-4-oxobut-2-en-2-yl)amino]-2-phenylacetate Chemical compound [K+].CCOC(=O)C=C(C)NC(C([O-])=O)C1=CC=CC=C1 QMWWAEFYIXXXQW-UHFFFAOYSA-M 0.000 claims description 6
- 238000011084 recovery Methods 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 229910000077 silane Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 28
- 238000006884 silylation reaction Methods 0.000 description 20
- 238000003756 stirring Methods 0.000 description 15
- 229960003022 amoxicillin Drugs 0.000 description 14
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 229960004920 amoxicillin trihydrate Drugs 0.000 description 13
- 239000010410 layer Substances 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- MASDFXZJIDNRTR-UHFFFAOYSA-N 1,3-bis(trimethylsilyl)urea Chemical compound C[Si](C)(C)NC(=O)N[Si](C)(C)C MASDFXZJIDNRTR-UHFFFAOYSA-N 0.000 description 3
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 150000003377 silicon compounds Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- MRFJAULKKHVIGF-OGFXRTJISA-N (2r)-2-amino-2-(4-hydroxyphenyl)acetyl chloride;hydrochloride Chemical compound Cl.ClC(=O)[C@H](N)C1=CC=C(O)C=C1 MRFJAULKKHVIGF-OGFXRTJISA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- MRFJAULKKHVIGF-UHFFFAOYSA-N 2-amino-2-(4-hydroxyphenyl)acetyl chloride;hydrochloride Chemical compound [Cl-].ClC(=O)C([NH3+])C1=CC=C(O)C=C1 MRFJAULKKHVIGF-UHFFFAOYSA-N 0.000 description 2
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 2
- LJCWONGJFPCTTL-UHFFFAOYSA-N 4-hydroxyphenylglycine Chemical compound OC(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- XMMFBEWONDCTLD-UHFFFAOYSA-N acetyl(dimethyl)azanium;chloride Chemical compound Cl.CN(C)C(C)=O XMMFBEWONDCTLD-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- XUZTXXZGJMGKTN-UHFFFAOYSA-N (2-amino-4-hydroxyphenyl) acetate Chemical compound CC(=O)OC1=CC=C(O)C=C1N XUZTXXZGJMGKTN-UHFFFAOYSA-N 0.000 description 1
- OPEGYZAATHKDEM-HCWXCVPCSA-N (2r,4s)-2-[(r)-carboxy(formamido)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid Chemical compound CC1(C)S[C@H]([C@H](NC=O)C(O)=O)N[C@H]1C(O)=O OPEGYZAATHKDEM-HCWXCVPCSA-N 0.000 description 1
- NVIAYEIXYQCDAN-MHTLYPKNSA-N (6r,7s)-7-azaniumyl-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(C)=C(C([O-])=O)N2C(=O)[C@H]([NH3+])[C@@H]12 NVIAYEIXYQCDAN-MHTLYPKNSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- MEAZEHJUPLREOQ-UHFFFAOYSA-N 2-amino-2-phenylacetyl chloride Chemical compound ClC(=O)C(N)C1=CC=CC=C1 MEAZEHJUPLREOQ-UHFFFAOYSA-N 0.000 description 1
- LRWFMQCGNBOTQP-UHFFFAOYSA-N 5,5-dimethyl-2-[[(2-phenylacetyl)amino]methyl]-1,3-thiazolidin-3-ium-4-carboxylate Chemical compound N1C(C(O)=O)C(C)(C)SC1CNC(=O)CC1=CC=CC=C1 LRWFMQCGNBOTQP-UHFFFAOYSA-N 0.000 description 1
- WNPVZANXRCPJPW-UHFFFAOYSA-N 5-[isocyano-(4-methylphenyl)sulfonylmethyl]-1,2,3-trimethoxybenzene Chemical compound COC1=C(OC)C(OC)=CC(C([N+]#[C-])S(=O)(=O)C=2C=CC(C)=CC=2)=C1 WNPVZANXRCPJPW-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- HBMCQTHGYMTCOF-UHFFFAOYSA-N hydroquinone monoacetate Natural products CC(=O)OC1=CC=C(O)C=C1 HBMCQTHGYMTCOF-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012009 microbiological test Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- LULXBAGMGMJJRW-UHFFFAOYSA-N n,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)CC(=O)N[Si](C)(C)C LULXBAGMGMJJRW-UHFFFAOYSA-N 0.000 description 1
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 150000001282 organosilanes Chemical class 0.000 description 1
- YCOFRPYSZKIPBQ-UHFFFAOYSA-N penicillic acid Natural products COC1=CC(=O)OC1(O)C(C)=C YCOFRPYSZKIPBQ-UHFFFAOYSA-N 0.000 description 1
- VOUGEZYPVGAPBB-UHFFFAOYSA-N penicillin acid Natural products OC(=O)C=C(OC)C(=O)C(C)=C VOUGEZYPVGAPBB-UHFFFAOYSA-N 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000005331 phenylglycines Chemical class 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 238000011172 small scale experimental method Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
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Opfindelsen angår en fremgangsmåde til fremstilling af 6-[D-a-amino-(p-hydroxyphenyl)acetamido]-penicillansyre (sædvanligvis betegnet amoxicillin) eller ikke-toxiske farmaceutisk acceptable salte deraf 5 ved acylering af 6-aminopenicillansyre i et med vand ublandbart inert organisk hovedopløsningsmiddel med en opløsning af et blandet anhydrid med den almene formel IIIThe invention relates to a process for the preparation of 6- [Da-amino- (p-hydroxyphenyl) acetamido] -penicillanic acid (usually termed amoxicillin) or non-toxic pharmaceutically acceptable salts thereof by acylation of 6-aminopenicillanic acid in a water-immiscible inert organic main solvent with a solution of a mixed anhydride of the general formula III
O 9 io H°\Cy CH - - o - c - RyO 9 io H ° \ Cy CH - - o - c - Ry
N -Η. IIIN -Η. III
*4‘ %:-c>* 4%: - c>
Ir5 Nr6 15 hvori betegner en alkoxygruppe med 1-2 carbonatomer,Ir5 No6 wherein an alkoxy group has 1-2 carbon atoms,
Rg betegner en alkoxygruppe med 1-3 carbonatomer, R^ betegner en alkylgruppe med 1-3 carbonatomer eller et hydrogenatom, og R^ betegner en alkylgruppe med 1-3 carbonatomer, hvilken opløsning af blandet anhydrid forud 20 er fremstillet ved omsætning af det tilsvarende Dane-salt med et alkylchlorformiat i et inert . organisk hovedopløsningsmiddel og under tilstedeværelse af en katalytisk mængde af en tertiær aminRg represents an alkoxy group of 1-3 carbon atoms, R ^ represents an alkyl group of 1-3 carbon atoms or a hydrogen atom, and R ^ represents an alkyl group of 1-3 carbon atoms, the solution of mixed anhydride preceded by reaction of the corresponding Dane salt with an alkyl chloroformate in an inert. organic major solvent and in the presence of a catalytic amount of a tertiary amine
En sådan fremgangsmåde til fremstilling af 6-[D-25 ά-amino- (p-hydroxyphenyl) acetamido] -penicillansyre kendes f.eks. fra Britisk Patentskrift nr. 1.339.605/som i eksemplerne 1-5 beskriver fremstillingen af denne forbindelse, men i udbytter, som gør fremstillingen økonomisk u-interessant (eksempel 1: 43% med en renhed på 80%, eksem-30pel 3: 20% med en renhed på 16%, eksempel 4: 37% med en renhed på 93%, medens der i slutningen af eksemplerne 2 og 5 Icon er påvist tilstedeværelse af ovennævnte forbindelse.)Such a process for the preparation of 6- [D-25β-amino- (p-hydroxyphenyl) acetamido] -penicillanic acid is known, e.g. from British Patent Specification No. 1,339,605 / which in Examples 1-5 describes the preparation of this compound but in yields which make the preparation economically unattractive (Example 1: 43% with a purity of 80%, Example 3: 20% with a purity of 16%, Example 4: 37% with a purity of 93%, while at the end of Examples 2 and 5 Icon a presence of the above compound was detected.)
En fremgangsmåde, som omfatter acylering af et forud silyleret cephalosporansyrederivat med et 35blandet anhydrid med den almene formel III, kendes fra f.eks. hollandsk patentansøgning nr. 6912811,A process comprising acylating a precylated cephalosporanoic acid derivative with a mixed anhydride of the general formula III is known from e.g. Dutch Patent Application No. 6912811,
Britisk Patentskrift nr. 1073530 og narvnlig fra Britisk Patentskrift nr. 1460914.British Patent Specification No. 1073530, and from British Patent Specification No. 1460914.
151024 2151024 2
Imidlertid kan fagmanden, specielt fra eksemplerne 3 og 13 i sidstnævnte Patentskrift, ikke tilstrækkelig sikkert udlede, at en acylering af f.eks. 7-amino-3-((1H) -1,2,3-triazol-5-yl) - thiomethyl-3-cephem-4-carboxyl-5 syre eller dens trimethylsilylderivat ved hjælp af f.eks. ethoxycarbonyl -D-α-(l-carbomethoxy-propen-2-yl)amino-p-hydroxyphenyl-acetat vil kunne udføres med økonomisk interessante udbytter.However, those skilled in the art, especially from Examples 3 and 13 of the latter patent, cannot sufficiently deduce that an acylation of e.g. 7-Amino-3 - ((1H) -1,2,3-triazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid or its trimethylsilyl derivative by e.g. ethoxycarbonyl-D-α- (1-carbomethoxy-propen-2-yl) amino-p-hydroxyphenyl acetate could be made with economically interesting yields.
Mere specielt synes i eksempel 13, side 10 21, omdannelsen af 0,02 mol 7-amino-3-(1,2,3-triazol -5-yl)-thiomethyl-3-cephem-4-carboxylsyre , som forud var omsat med 0,06 mol trimethylchlorsilan under tilstedeværelse af 0,06 mol af en ca. 2:l-blanding af triethylamin og Ν,Ν-dimethylanilin, med en reaktionsblanding fremstillet 15 på sædvanlig måde i acetonitril udfra 0,05 mol af Dane-saltet og ethylchlorformiat,. kun at føre til temmeligt utilfredsstillende udbytter, (se f.eks. side 21, linie 38 i forbindelse med linierne 5-10 på samme side).More particularly, in Example 13, page 10 21, the conversion of 0.02 moles of 7-amino-3- (1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, reacted with 0.06 mol of trimethyl chlorosilane in the presence of 0.06 mol of a ca. 2: 1 mixture of triethylamine and Ν, Ν-dimethylaniline, with a reaction mixture prepared in the usual manner in acetonitrile from 0.05 mole of the Dane salt and ethyl chloroformate. only to lead to rather unsatisfactory yields (see, for example, page 21, line 38 in connection with lines 5-10 on the same page).
Også anden patentlitteratur vedrørende fremstil-20 ling af denne type cephalosporansyrederivater angiver kun økonomisk utilfredsstillende fremgangsmåder, f.eks. USA-patentskrift B 516.047, eks. 1, spalte 7, linie 44, eks.Also, other patent literature on the preparation of this type of cephalosporanoic acid derivatives discloses only economically unsatisfactory methods, e.g. U.S. Patent B 516,047, Example 1, Column 7, Line 44, Ex.
5A, linie 52 og eks. 6, og USA-patentskrift 3946003, eks.5A, line 52 and Example 6, and U.S. Patent 3946003, Ex.
1 (spalte 11, linie 65) og eks. 3 (spalte 12, linie 62).1 (column 11, line 65) and example 3 (column 12, line 62).
25 Endvidere synes det ifølge spalte 4, linie 1-5 og eks. 1, (spalte 10) nødvendigt først at silylere de phenoliske p-hydroxygrupper til opnåelse af praktiske resultater, hvilken nødvendighed endvidere fremgår af eks.Furthermore, according to column 4, lines 1-5 and example 1 (column 10), it appears necessary to first silylate the phenolic p-hydroxy groups to obtain practical results, which necessity is furthermore apparent from example.
1 på side 13 og 14 af tysk paténtansøgning nr. DT-2600880 30 og fra eksemplerne 1-5 i tysk patentansøgning DT-2626280, US patent 3946003, eksempel 1 og belgisk patent 840060, eksempel 10.1 on pages 13 and 14 of German Patent Application No. DT-2600880 30 and from Examples 1-5 of German Patent Application DT-2626280, US Patent 3946003, Example 1 and Belgian Patent 840060, Example 10.
Derfor har det været mindre atraktivt for fagfolk at udvikle den fremgangsmåde, som er beskrevet if.Therefore, it has been less attractive to those skilled in the art to develop the method described in.
35 eks. britisk patentskrift nr. 1.339.605, end at søge efter alternative acyleringsmetoder i forsøg på at finde en ny og forbedret fremgangsmåde til fremstilling af de ønskede forbindelser med et økonomisk tilfredsstillende udbyt- 151024 3 te og en relativ stor renhed. Et yderligere krav til fremgangsmåden er med henblik på dens anvendelse i industriel målestok endvidere, at de uundgåelige urenheder fjernes på en billig og enkel måde til opnåelse af den 5 renhedstilstand/ som kræves af sundhedsmyndighederne.35 British Patent No. 1,339,605, than searching for alternative acylation methods in an attempt to find a new and improved process for preparing the desired compounds with an economically satisfactory yield and a relatively high purity. A further requirement of the method is, for its use on an industrial scale, that the inevitable impurities are removed in an inexpensive and simple way to obtain the purity state / required by the health authorities.
Det er kendt fra litteraturen at fremstille peni-cillansyre =- og cephalosporansyrederivater ved acylering af 6-APA eller 7-A(D)CA og deres derivater med hydrochlori-det af 2-phenylglycinchlorid og derivater deraf med en 10 substitueret phenylgruppe, idet nævnte syrechlorid fås ved at omsætte den substituerede phenylglycin med reagenser såsom phosphorpentachlorid, thionylchlorid eller phos-gen. Selvom forbedrede fremgangsmåder til fremstilling af D-(-)-2-(p-hydroxyphenyl)glycylchlorid-hydrochlorid og 15 det krystallinske · hemidioxansolvat deraf kendes fra de britiske patentskrifter nr. 1460915 og nr. 1466637, har acyleringen af 6-APA eller 7A(D)CA eller deres 3-methyl-modifikationer med ovennævnte acyleringsmiddel ikke hidtil ført til de ønskede resultater, navnlig som følge af 20 at produktet enten har været for urent til at gøre en udvinding i den ønskede renhedsgrad realistisk, eller som følge af at udgangsmaterialetD-2- (p-hydroxyphenyl) -g lycyl** chlorid-hydrochlorid i den nødvendige kvalitet (renhed), hvis dette overhovedet har været tilgængeligt, har været 25 for kostbart. De dannede urenheder, som findes, hvis der anvendes et syrechlorid-hydrochlorid, som er indkøbt til acceptable priser, synes at bekræfte angivelserne om ledsagende urenheder i slutproduktet og de lave udbytter af den temmelig beslægtede acy lering med d- (-) -2- (p-hydroxy-30 phenyl)glycyl-chlorid-hydrochlorid af 7-amino-cephalospor-ansyrederivater ifølge britisk patentskrift nr. 1460916 (eksempler 2,4 og 9, specielt side 17, linie 32-34 og eksempel 8, som angår yderligere rensning af det ønskede produkt) og britisk patentskrift nr. 1460914 (eksempel 3, 35 5, 9 og 10) ., Tysk patentansøgning nr. DT2520647 angiver i denne forbindelse på side 2, linie 10-20 endvidere, at anvendelse af de sædvanligt benyttede acyleringsmidler så- 151024 4 som syrehalogenider ved amoxib.illinsynthese ikke kommer i betragtning. Fra tysk patentansøgning nr. DT 2611286 kendes en fremgangsmåde til fremstilling af amoxicillin-tri-hydrat omfattende acylering af forudsilyleret 6-APA med 5 J>(-)-2-(p-hydroxyphenyl) glycyl-chlorid-hydrochlorid, som fører til udbytter, der synes i nogen qrad at nærme sier de krav, der stilles i praksis.It is known from the literature to prepare penicillinic acid and cephalosporanoic acid derivatives by acylation of 6-APA or 7-A (D) CA and their derivatives with the hydrochloride of 2-phenylglycine chloride and derivatives thereof with a substituted phenyl group, said acid chloride is obtained by reacting the substituted phenylglycine with reagents such as phosphorus pentachloride, thionyl chloride or phosgene. Although improved processes for preparing D - (-) - 2- (p-hydroxyphenyl) glycyl chloride hydrochloride and the crystalline hemidioxane solvate thereof are known from British Patent Nos. 1460915 and No. 1466637, the acylation of 6-APA or 7A has (D) CA or their 3-methyl modifications with the above acylating agent have not so far led to the desired results, in particular because the product has either been too impure to make a recovery in the desired degree of purity realistic, or because the starting material D-2- (p-hydroxyphenyl) -g lycyl ** chloride hydrochloride of the necessary quality (purity), if available at all, has been too expensive. The impurities formed, if used with an acid chloride hydrochloride purchased at acceptable prices, seem to confirm the indications of accompanying impurities in the final product and the low yields of the fairly related acylation with d- (-) -2- (p-hydroxy-phenyl) glycyl chloride hydrochloride of 7-amino-cephalosporic anhydride derivatives according to British Patent Specification No. 1460916 (Examples 2.4 and 9, especially pages 17, lines 32-34 and Example 8, which further relates to purification of the desired product) and British Patent Specification No. 1460914 (Examples 3, 35, 5, 9 and 10). German Patent Application No. DT2520647 further states in this connection on page 2, lines 10-20 that use of the commonly used acylating agents such as acid halides for amoxibillin synthesis are not considered. German Patent Application No. DT 2611286 discloses a process for the preparation of amoxicillin trihydrate comprising acylation of predilylated 6-APA with 5 J (-) - 2- (p-hydroxyphenyl) glycyl chloride hydrochloride leading to yields , which in any qrad seems to approach the requirements that are put into practice.
Ved fremstillingen af dette udgangsmateriale i-følge f.eks. de britiske patentskrifter nr. 1460915 og nr.In the preparation of this starting material, e.g. British Patent Nos. 1460915 and Nos.
10 1466637 anvendes der imidlertid phosgen ved en forholdsvis vanskelig håndterbar proces, ved hvilken et fast stof omsættes med en gas. En sådan udøvelse er særdeles kostbar i et stort antal lande med meget strenge sikkerhedsregler og visse steder uigennemførlig. Af samme grund, la-15 des fremgangsmåden, som beskrives i britisk patentskrift nr. 1268536 og nr. 1341827, ved hvilken 6-isocyanatpeni-cillansyre- og 7-isocyanatcephalosporansyrederivater fremstilles udfra 6-APA-og 7-A(D)CA-estere med phosgen og påfølgende omsætning med penicilliner eller cephalospori-20 ner, ude af betragtning til fremstilling af amoxicillin.However, phosgene is used in a relatively difficult to handle process in which a solid is reacted with a gas. Such an exercise is extremely costly in a large number of countries with very strict safety rules and in some places impracticable. For the same reason, the process described in British Patent Nos. 1268536 and 1341827 wherein 6-isocyanate penicillic acid and 7-isocyanate cephalosporanoic acid derivatives are prepared from 6-APA and 7-A (D) CA phosgene esters and subsequent reaction with penicillins or cephalosporins, irrespective of amoxicillin production.
På den anden side omhandler f.eks. tysk patentansøgning nr. 2520647 en fremgangsmåde til fremstilling af cc-aminoacylpenicillansyrederivater og bl.a. amoxicillin, ved hvilken 25 . (i) 6-APA bringes i kontakt med et over skud af en stærk tertiær aminbase (f.eks. triethylamin) i et indifferent, vanduopløseligt, organisk opløsningsmiddel (f.eks. methylenchlorid eller chloroform), resulterende i en opløsning af et salt af 6-APA med basen i nævn-30 te opløsningsmiddel, (ii) den tilbageværende stærke tertiære aminbase neutraliseres i opløsningsmidlet, f.eks. ved tilsætning af N,N-dimethylacetamid-hydrochlorid, (iii) den opnåede neutraliserede opløs-35 ning bringes i kontakt med en opløsning af et blandet an- hydrid af en kortkædet alkoxymyresyre og et N-beskyttet derivat af D-2-amino-p-hydroxyphenyleddikesyre, i hvilket 151024 5 den N-beskyttende gruppe er labil for syre, i et vanduop-løseligt, indifferent,. .organisk opløsningsmiddel ved en temperatur mellem -50°C og +30°C, fortrinsvis mellem ; -30°C og 0°C, resulterende i en opløsning af et N-beskyt-5 tet amoxicillinderivat, (iv) den således opnåede opløsning bringes i kontakt med vand og en stærk syre (såsom saltsyre eller p-toluensvovlsyre) ved stuetemperatur eller afkøles, f.eks. til 0°C/til fjernelse af den syrelabile N-be- 10 skyttende gruppe, og (v) det således opnåede amoxicillin isoleres fra det således dannede vandige system.On the other hand, e.g. German patent application No. 2520647 discloses a process for the preparation of cc-aminoacylpenicillanic acid derivatives and, inter alia, amoxicillin, at which 25. (i) 6-APA is contacted with an excess shot of a strong tertiary amine base (e.g., triethylamine) in an inert, water-insoluble organic solvent (e.g., methylene chloride or chloroform), resulting in a solution of a salt (ii) neutralizing the remaining strong tertiary amine base in the solvent, e.g. by adding N, N-dimethylacetamide hydrochloride, (iii) contacting the obtained neutralized solution with a solution of a mixed anhydride of a short chain alkoxy formic acid and an N-protected derivative of D-2-amino acid. p-hydroxyphenylacetic acid, in which the N-protecting group is labile to acid, in a water-insoluble, inert. organic solvent at a temperature between -50 ° C and + 30 ° C, preferably between; -30 ° C and 0 ° C, resulting in a solution of an N-protected amoxicillin derivative, (iv) contacting the solution thus obtained with water and a strong acid (such as hydrochloric acid or p-toluene sulfuric acid) at room temperature or cool, e.g. to 0 ° C / to remove the acid-labile N-protecting group and (v) the amoxicillin thus obtained is isolated from the aqueous system thus formed.
Mindre tiltrækkende omstændigheder ved denne fremgangsmåde er bl.a.,at fremgangsmåden udføres ved la-15 ve koncentrationer, at opløsningsmidlerne blandes,således at genvinding deraf bliver mere vanskelig, og at der, ved tilsætning af dimethylacetamid-hydrochloridet som følge af lokalt store koncentrationer, nogle gange sker udkrystallisation af 6-APA, 7-ADCA eller 7-ACA eller derivater 20 deraf, således at der kræves et meget nøjagtigt doserings-system.Less attractive circumstances of this process are, inter alia, that the process is carried out at low concentrations, that the solvents are mixed so that recovery thereof becomes more difficult and that, by adding the dimethylacetamide hydrochloride due to locally high concentrations , sometimes, crystallization of 6-APA, 7-ADCA or 7-ACA or derivatives 20 occurs, so that a very accurate dosing system is required.
Endvidere angår et antal patentbeskrivelser fremstillingsmetoder til a-aminoacylpenicillansyrederivater ved acylering af 6-APA med blandede anhydrider afledt fra 25 modificerede Dane-salte af D-2-amino-(p-hydroxyphenyl) ed-.i. dikesyre, f.eks. sådanne som er beskrevet i de tyske patentansøgninger nr. 1.302.847, 2.020.133 og 2.065.879 og de britiske patentskrifter nr, 1.327.270 og 1.347.979.Furthermore, a number of patent disclosures relate to preparation methods for α-aminoacylpenicillanic acid derivatives by acylation of 6-APA with mixed anhydrides derived from 25 modified Dane salts of D-2-amino- (p-hydroxyphenyl) ed-i. diacetic acid, e.g. such as are disclosed in German patent applications Nos. 1,302,847, 2,020,133 and 2,065,879 and British Patent Nos. 1,327,270 and 1,347,979.
Imidlertid er de udbytter, som fås med sådanne 30 Dane-salte, utilfredsstillende, og de pågældende Dane-sal-te er ikke kommercielt tilgængelige.However, the yields obtained with such Dane salts are unsatisfactory and the Dane salts in question are not commercially available.
Hollandsk patentansøgning nr. 6.401.841 angår beskyttelse af carboxylgruppen i 6-APA, 7-ACA og andre aminosyrer ved omsætning med dihalogensilanderivater. Sådanne 35 bi-funktionelle sdliciumforbindelser er lettere tilgængelige end de mono-funktionelle trialkylhalogensilaner,o.g deres anvendelse skulle i et antal tilfælde føre til bed- 151024 6 re udbytter, som det f.eks. fremgår af britisk patent-skrift nr. 1.266.544, som angår fremstillingen af som mellemprodukter egnede organos i lanpenicillianer ved omsætning ' af 6-APA og de bi-funktionelle siliciumforbindelser.Dutch Patent Application No. 6,401,841 relates to protection of the carboxyl group of 6-APA, 7-ACA and other amino acids by reaction with dihalogen silane derivatives. Such bi-functional silicon compounds are more readily available than the mono-functional trialkyl halogen silanes, and their use should, in a number of cases, result in better yields, such as e.g. is disclosed in British Patent Specification No. 1,266,544, which relates to the preparation of intermediate-suitable organos in lanpenicillians by reaction of 6-APA and the bi-functional silicon compounds.
5 Organosilanderivaterne acyleres f.eks. til ampicillin, således at fagmanden udfra indholdet af denne patentbeskrivelse ville forvente, at anvendelsen af de i patentbeskrivelsen nævnte organosilanpenicilliner også ville føre til gode udbytter ved fremstilling af amoxicillin.For example, the organosilane derivatives are acylated. to ampicillin so that those skilled in the art would expect from the content of this patent disclosure that the use of the organosilane penicillins mentioned in the patent specification would also result in good yields in the preparation of amoxicillin.
10 Imidlertid kunne denne forventning overraskende ikke bekræftes ved orienterende forsøg.10 Surprisingly, however, this expectation could not be confirmed by orientation experiments.
Fra senere patentbeskrivelser, f.eks. de britiske patentbeskrivelser nr. 1.356.737, 1.404.846 og 1.459.999, er det kendt at anvende trivalente phosphorderivater i 15 stedet for ovennævnte siliciumderivater. Ulemper ved disse derivater er navnlig, at deres pris er 10-20 gange større, og dette i kombination med de di (lavere) alkylphos-phordarivaters toxicitet og evne til spontant at bryde i brand, som anført i Inorganic Synthesis 15 (1974), side 20 191-193, gør phosphorforbindelseme til en dårlig erstat ning for siliciumforbindelserne.From later patent descriptions, e.g. In British Patent Specifications Nos. 1,356,737, 1,404,846 and 1,459,999, it is known to use trivalent phosphorus derivatives in place of the above-mentioned silicon derivatives. In particular, disadvantages of these derivatives are that their price is 10-20 times greater, and this in combination with the toxicity and ability of spontaneously combustible di (lower) alkylphosphorus derivatives, as stated in Inorganic Synthesis 15 (1974), pages 20 191-193, make the phosphorus compounds a poor substitute for the silicon compounds.
Yderligere er det kendt fra et antal patentbeskrivelser, f.eks. de japanske patentansøgninger nr.Further, it is known from a number of patent disclosures, e.g. Japanese patent applications no.
49-014.687 og 49-048.892, og de britiske patentskrifter 25 nr. 1.367.342 og 1.382.255 og de tyske.patentansøgninger nr. 2.460.649 og 2.621.618, at fremstille amoxicillin udfra 6-APA og p-hydroxyphenylglycin eller lavere alkyl-estere deraf ved enzymatisk acylering, men processer af denne type er også utilfredsstillende med hensyn til det 3 o opnåede udbytte og/eller som følge af at der er acyle-' rings enzym til stede i den opnåede amoxicillinholdige opløsning.49-014,687 and 49-048,892, and British Patents 25 Nos. 1,367,342 and 1,382,255 and German Patent Nos. 2,460,649 and 2,621,618, to prepare amoxicillin from 6-APA and p-hydroxyphenylglycine or lower alkyl esters thereof by enzymatic acylation, but processes of this type are also unsatisfactory with respect to the yield obtained and / or due to the presence of acylation enzyme in the obtained amoxicillin-containing solution.
Som resultat af et omfattende forsknings-og ud-vikingsarbejde er der nu fundet en forbedret fremgangsmåde 35 til fremstilling af amoxicillin, hvilken fremgangsmåde ifølge opfindelsen er ejendommelig ved, at a) 6-aminopenicillansyre omsættes i et tørt, inert, med vand ublandbart hovedopløsningsmiddel med 151024 7 et trialkylsilylgruppetilførende silyleringsmiddel i en mængde svarende til ca. 2 ækvivalenter i forhold til 6-aminopenicillansyren, idet eventuelle tilstedeværende mængder fri trialkylhalogensilan, med 1-3 carbonatomer 5 i alkylgrupperne, og tertiær amin i reaktionsblandingen er indbyrdes afpasset ved justering ved reaktionens afslutning efter en empirisk bestemt signalværdi som defineret i beskrivelsen, b) den opnåede reaktionsblanding, som indeholder 10 et derivat af 6-aminopenicillansyre med formlen: s /\ H2N-CH-CH C(CHj),As a result of extensive research and development work, an improved process 35 for the preparation of amoxicillin has now been found, which process of the invention is characterized in that a) 6-aminopenicillanic acid is reacted in a dry, inert, water-immiscible main solvent with A trialkylsilyl group-applying silylating agent in an amount corresponding to approx. 2 equivalents to the 6-aminopenicillanoic acid, any amounts of free trialkyl halogen silane present, having 1-3 carbon atoms 5 in the alkyl groups, and tertiary amine in the reaction mixture being mutually matched at the end of the reaction after an empirically determined signal value as defined in the description, b) the reaction mixture obtained containing a derivative of 6-aminopenicillanic acid of the formula: s / H 2 N-CH-CH C (CH 2),
IIIIII
C-N-CH - COO - Si -RC-N-CH - COO - Si -R
OISLAND
15 * ' og/eller /S\15 * 'and / or / S \
Ra-Si - NH - (Ή-CH * C(CHi)j 20 --N-CH-COO-Si-R^ „ ° · ^R.Ra-Si - NH - (Ή-CH * C (CHi) j) --N-CH-COO-Si-R
II · hvori R^, R2 og R^ betegner ens eller forskellige alkyl-grupper med 1-3 carbonatomer og hver fortrinsvis beteg-25 ner en methylgruppe, afkøles og derpå hurtigt under vandfri betingelser, blandes med en afkølet opløsning af i det mindste en ækvimolær mængde af et blandet anhydrid med formlen III, hvilken opløsning er fremstillet ved omsætning af det tilsvarende Dane-salt med et alkylchlor-30 formiat under vandfri betingelser i et med vand ublandbart, inert, organisk hovedopløsningsmiddel, hvortil er sat 0-25 volumen% af et indifferent co-opløsnings-middel, hvorefter c) acyleringsreaktionen fortsættes ved en tempe-35 ratur under 0°C, efterfulgt af udvinding af den ønskede forbindelse på i sig selv kendt måde.II, wherein R 1, R 2 and R 2 represent the same or different alkyl groups of 1-3 carbon atoms and each preferably represents a methyl group, cooled and then rapidly under anhydrous conditions, mixed with a cooled solution of at least one equimolar amount of a mixed anhydride of formula III prepared by reacting the corresponding Dane salt with an alkyl chloroformate under anhydrous conditions in an immiscible, inert, inorganic main solvent, to which is added 0-25% by volume of the inert co-solvent, after which c) the acylation reaction is continued at a temperature below 0 ° C, followed by recovery of the desired compound in a manner known per se.
Reaktionen fortsættes fortrinsvis ved -20 til -30°C i fra 1/4 til 3 timer og fortrinsvis i fra 1 til 151024 8 2,5 timer, og reaktionsblandingen udhældes i vand, idet pH-værdien omhyggeligt holdes under 2,5. Fortrinsvis holdes pH mellem 0,8 og 1,2.The reaction is preferably continued at -20 to -30 ° C for from 1/4 to 3 hours and preferably from 1 to 15 hours, and the reaction mixture is poured into water, carefully maintaining the pH below 2.5. Preferably, the pH is maintained between 0.8 and 1.2.
Det tørre, inerte, med vand ikke blandbare op-5 løsningsmiddel som anvendes ved silyleringsreaktionen er fortrinsvis tør methylenchlorid, og silyleringsmidlet er fortrinsvis trimethylchlorsilan (TMCS) under tilstedeværelse af en tertiær amin. Imidlertid kan der også opnås gode resultater med trimethylsilylacetamid, 10 bis(trimethylsilyl)acetamid, bis(trimethylsilyl)urinstof og hexamethyldisilazan.The dry, inert, water-immiscible solvent used in the silylation reaction is preferably dry methylene chloride, and the silylating agent is preferably trimethyl chlorosilane (TMCS) in the presence of a tertiary amine. However, good results can also be obtained with trimethylsilylacetamide, 10 bis (trimethylsilyl) acetamide, bis (trimethylsilyl) urea and hexamethyldisilazane.
Udtrykket "indbyrdes afpasset", der anvendes i beskrivelsen af trin (a) ovenfor og i krav 1 kan forklares som følger.The term "mutually matched" used in the description of step (a) above and in claim 1 can be explained as follows.
15 Det har vist sig, at der kun kan fås optimale slutudbytter på reproducerbar måde ved anvendelse af en meget nøje balance mellem mængderne af midler som benyttes til frembringelse af det silylerede mellemprodukt, specielt med hensyn til den ønskede optimale 20 reaktion med den fremstillede opløsning af det blandede Dane-anhydrid. Det vil for fagmanden være klart, at der (for blot at pege på hovedårsagerne til uønskede afvigelser fra den ideelle balance) i praksis uundgåeligt vil forekomme små fejl ved udmåling af volume-25 ner eller afvejning af mængder, specielt ved forsøg i meget lille målestok (nogle få mmol) samt ved produktion i stor industriel målestok, ligesom der er urenheder i reagenser af teknisk kvalitet. Der er derfor behov for en måde, hvorpå den nødvendige balance kan 30 kontrolleres in situ og om nødvendigt genoprettes efter afslutning af silyleringen. Nødvendigheden og fordelen af at måle denne gensidige balance og dens eventuelle genoprettelse er et alment træk ved sily-leringsmetoder som udføres på 6-aminopenicillansyre 35 og lignende, men den er af helt overvejende betydning, når silyleringen udføres med den mest økonomiske kombination af midler, f.eks. trimethylchlorsilan og tri-ethylamin, da en sådan kombination - i modsætning til 151024 9 enkeltmidler til silylering, såsom N,0-bistrimethyl-silyl-acetamid - ikke selv tilvejebringer nogen form for indre gensidig ballance.It has been found that only optimal final yields can be obtained in a reproducible manner by using a very close balance between the amounts of agents used to produce the silylated intermediate, especially with respect to the desired optimal reaction with the solution prepared. the mixed Dane anhydride. It will be appreciated by those skilled in the art that (merely to point out the main causes of unwanted deviations from the ideal balance), in practice, small errors in measuring volumes or weighing volumes will inevitably occur, especially in small scale experiments. (a few mmol) as well as large scale industrial production, as well as impurities in technical grade reagents. Therefore, there is a need for a way in which the necessary balance can be checked in situ and, if necessary, restored after completion of the silylation. The necessity and advantage of measuring this mutual balance and its possible restoration is a common feature of silylation methods performed on 6-aminopenicillanic acid 35 and the like, but it is of paramount importance when the silylation is performed with the most economical combination of agents, eg. trimethylchlorosilane and triethylamine, since such a combination - unlike single silylation agents such as N, O-bistrimethylsilylacetamide - does not itself provide any kind of internal mutual balance.
I søgning efter en egnet og samtidig simpel 5 metode ved hvilken denne balance kan måles og om nødvendigt korrigeres in situ under teniske betingelser, viste det sig overraskende, at f.eks. anvendelse af en god kvalitet pH-meter i tilstrækkelig grad opfyldte dette behov. Hvis man f.eks. anvender et Radiometer 10 pH-meter type TTT2,C i forbindelse med en Radiometer GK 240lC-elektrode eller en Ingold, såkaldt kold elektrode ved en temperatur mellem 15 og 25°C, skal der opnås en pH-skalavaerdi i det empiriske område mellem 5,5 og 7,5, og fortrinsvis mellem 6,0 og 7,2,ved af-15 slutningen af silyleringsreaktionen. Hvis dette ikke er tilfældet tilsættes en lille mængde yderligere tri-methylchlorsilan eller f.eks. triethylamin til opnåelse af en forbedret indbyrdes balance.In searching for a suitable and at the same time simple method by which this balance can be measured and, if necessary, corrected in situ under tenic conditions, it was surprisingly found that e.g. using a good quality pH meter adequately met this need. For example, if using a Radiometer 10 pH meter type TTT2, C in conjunction with a Radiometer GK 240lC electrode or an Ingold, so-called cold electrode at a temperature between 15 and 25 ° C, a pH scale value must be obtained in the empirical range between 5 , 5 and 7.5, and preferably between 6.0 and 7.2, at the end of the silylation reaction. If this is not the case, a small amount of additional trimethyl chlorosilane is added or e.g. triethylamine to achieve an improved balance.
Det har vist sig at være uden betydning om 20 · ovenfor anførte optimale pH-skalainterval faktisk svarer til et virkeligt pH-interval af samme størrelsesorden (6,0-7,2) ved måling efter opløsning af silylerings-blandingen i vand, da skalaintervalaflæsninger på andre egnede pH-metre kan justeres til den der fås med den 25 anførte pH-metertype. Det er derfor et træk ved opfindelsen at erkende behovet for regulering af den gensidige balance mellem midlerne i silyleringsreaktionen såvel som at foreskrive en simpel metode til at løse dette problem in situ.It has been found to be irrelevant whether the 20 · above optimum pH scale interval actually corresponds to an actual pH range of the same magnitude (6.0-7.2) when measuring after dissolving the silylation mixture in water, since scale interval readings on other suitable pH meters can be adjusted to that available with the 25 pH meter specified. Therefore, it is a feature of the invention to recognize the need for regulation of the mutual balance of the agents in the silylation reaction as well as to provide a simple method to solve this problem in situ.
30 Silyleringen udføres fortrinsvis i tør dichlor- methan under anvendelse af ca. to ækvivalenter af en tertiær amin som hydrogenchloridbindende middel, såsom triethylamin, og ca. to ækvivalenter af en trialkyl-halogensilan, såsom trimethylchlorsilan pr. mol 6-amino-35 penicillansyre under industrielle betingelser.The silylation is preferably carried out in dry dichloromethane using approx. two equivalents of a tertiary amine as a hydrogen chloride binding agent such as triethylamine, and ca. two equivalents of a trialkyl halo silane such as trimethyl chlorosilane per moles of 6-amino-penicillanic acid under industrial conditions.
Det tørre, vanduopløselige hovedopløsningsmiddel,son anvendes til fremstillingen af det såkaldte Dane-anhydrid kan være tør methylenchlorid,hvortil der som coopløs- 151024 10 ningsmiddel er sat dimethyIformamid, sulfolan, tetrahy-drofuran, methyl-2-pyrrolidon, 1,4-dioxan, acetonitril, dimethylacetamid eller tetramethylurinstof eller en blanding deraf i en mængde på højest 25 volumen-%, eller me-5 thylisobutylketon eller tetrahydrofuran som hovedopløsningsmiddel ,hvortil et eller flere af de nævnte coopløs-ningsmidler eventuelt kan være tilsat i mængder på op til 25 volumen %. Fortrinsvis omsættes kalium-eller natruim-D-a-(l-carbomethoxy-propen-2-yl)-amino-p-hydroxyphenyl-10 acetat med fortrinsvis methylchlorformiat i modsætning til hintidige angivelser, se f .eks. Houben-Weyl, Methoden der Organischen Chemie, 4. udgave (1974) bind XV/2, Syn-these von Peptiden, del II, side 172. N-methylmorpholin anvendes fortrinsvis som katalysator. Det anvendte chlor-15 formiat sættes fortrinsvis til det som udgangsmateriale anvendte Dane-salt,og reaktionen uføres fortrinsvis ved en temperatur på -10°C eller lavere, fortrinsvis ved en temperatur mellem -10°C og -35®C. Blandingerne af me-thylenchlorid og de angivne coopløsningsmidler med op 20 til ca. 20 volumen-% og fortrinsvis op til 10 volumen-% coopløsningsmiddel i udgangsblandingen foreslås som de optimale opløsningsmidler til fremstilling af det blandede Dane-anhydrid.The dry, water-insoluble main solvent used for the preparation of the so-called Dane anhydride may be dry methylene chloride, to which is added co-solvent dimethylformamide, sulfolane, tetrahydrofuran, methyl-2-pyrrolidone, 1,4-dioxane , acetonitrile, dimethylacetamide or tetramethylurea or a mixture thereof in an amount not exceeding 25% by volume, or methylisobutyl ketone or tetrahydrofuran as the main solvent, to which one or more of the said co-solvents may optionally be added in amounts up to 25 volume%. Preferably, potassium or natrum D-α- (1-carbomethoxy-propen-2-yl) -amino-p-hydroxyphenyl-acetate is reacted with preferably methyl chloroformate, contrary to the present disclosure, see e.g. Houben-Weyl, Methods der Organischen Chemie, 4th edition (1974) Volume XV / 2, Synthes von Peptide, Part II, page 172. N-methylmorpholine is preferably used as a catalyst. The chloroformate used is preferably added to the Dane salt used as the starting material, and the reaction is preferably carried out at a temperature of -10 ° C or lower, preferably at a temperature between -10 ° C and -35 ° C. The mixtures of methylene chloride and the indicated co-solvents with up to 20 to approx. 20% by volume and preferably up to 10% by volume co-solvent in the starting mixture are proposed as the optimal solvents for preparing the mixed Dane anhydride.
Fortrinsvis anvendes tetrahydrofuran, Ν,Ν-dime-25 thylacetamid, N,N-dimethylformamid, N-methylpyrrolidon og Ν,Ν,Ν* ,li'-tetramethylurinstof som coopløsningsmiddel.Preferably, tetrahydrofuran, Ν, Ν-dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidone and Ν, Ν, Ν *, 1'-tetramethylurea are used as co-solvent.
Ved en yderligere foretrukken fremgangsmåde afkøles opløsningen af anhydridet til en temperatur på -15°C eller.lavere, og en afkølet opløsning af silyleret 6-ΑΡΆ, .In a further preferred process, the solution of the anhydride is cooled to a temperature of -15 ° C or lower, and a cooled solution of silylated 6-ΑΡΆ.
30 7-ACA eller 3-methylmodifikationer heraf, tilsættes hurtigt under så effektiv omrøring som muligt, således at der holdes en temperatur mellem -15° og -30°C, hvorpå reaktionsblandingen omrøres i yderligere 0,5-3 timer. Det foretrækkes at anvende et lille overskud af forbindelsen 35 III.30 7-ACA or 3-methyl modifications thereof are added rapidly with as efficient stirring as possible, maintaining a temperature between -15 ° and -30 ° C, then stirring the reaction mixture for an additional 0.5-3 hours. It is preferred to use a small excess of compound 35 III.
Reaktionsblandingen blandes derpå fortrinsvis ned fortyndet opløsning af en uorganisk syre, såsan en fortyndet vandig saltsyre, fortrinsvis således at temperaturen andrager 151024 11 mellem -5° og +5°C og fortrinsvis ca. 0°C, og pH-værdien bliver 1,0 til 1,5. Blandingen omrøres i yderligere 0,5 til 2 timer ved samme temperatur.The reaction mixture is then preferably mixed down with dilute solution of an inorganic acid such as a dilute aqueous hydrochloric acid, preferably such that the temperature is between -5 ° and + 5 ° C and preferably approx. 0 ° C and the pH becomes 1.0 to 1.5. The mixture is stirred for an additional 0.5 to 2 hours at the same temperature.
Ved den foretrukne udførselsform adskilles lagene.In the preferred embodiment, the layers are separated.
5 Det vandige lag, som indeholder den ønskede forbindelse som hydrochloridet, vaskes med et indifferent, vanduop-løseligt, organisk opløsningsmiddel, f.eks. methyl-iso-butylketon eller methylenchlorid. Det organiske lag vaskes med vand, og vaskevandet ekstraheres med det orga-10 niske vaskemedium. Det vandige vaskemedium sættes til det vaskede, vandige lag, . Det v ndige lag holdes på en temperatur af 0°C eller lavere, og amoxicillin udvindes ved krystallisation på sædvanlig måde.The aqueous layer containing the desired compound as the hydrochloride is washed with an inert, water-insoluble organic solvent, e.g. methyl iso-butyl ketone or methylene chloride. The organic layer is washed with water and the wash water is extracted with the organic washing medium. The aqueous washing medium is added to the washed aqueous layer,. The aqueous layer is kept at a temperature of 0 ° C or lower and amoxicillin is recovered by crystallization in the usual manner.
Selvsagt kan det først isolerede amoxicillintri-15 hydrat omdannes til ikke-toxiske, farmaceutisk .acceptable salte efter i sig selv kendte fremgangsmåder.Of course, the first isolated amoxicillin trihydrate can be converted into nontoxic, pharmaceutically acceptable salts by methods known per se.
Det vil fremgå, at nogle af de vigtigste fordele ved acyleringsfremgangsmåden ifølge opfindelsen er: - forudgående selektiv silylering af p-hydroxy-20 gruppen i p-hydroxyphenylglycin undgås, - reaktionen udføres i en koncentreret opløsning af reaktanterne, således at man med et givet udstyr får et større udbytte i kg pr. charge, - anvendelse af et p-hydroxyphenylglycylchlorid-25 hydrochlorid undgås, hvilken forbindelse kun kan fremstilles efter en fremgangsmåde, som er vanskeligt gennemførlig og endvidere er temmelig kostbar i mange lande som følge af disses strenge sikkerhedsbestemmelser, om der overhovedet kan opnås tilladelse til fremstillingen 30 af forbindelsen, - anvendelse af store mængder andre hjælpekemikalier undgås, - det ønskede slutprodukt kan overraskende fremstilles i økonomisk fordelagtige initialudbytter i en 35 kvalitet, som er acceptabel under de eksisterende sundhedsbestemmelser, samtidig med at antallet af rensetrin kan reduceres med heraf følgende mindre tab af ønsket forbindelse, 151024 12 - blanding af det foretrukne vandublandbare hovedopløsningsmiddel, f.eks. dichlormethan, med en meget mindre mængde af et dipolært aprotisk, med vand blandbart opløsningsmiddel muliggør en simpel og økono- 5 misk fordelagtig genvinding af hovedopløsningsmidlet, - risikoen for uønsket og uventet krystallisation af 6-APA er praktisk taget ikke til stede, således at fremgangsmåden er pålidelig og temmelig problemløs.It will be appreciated that some of the key advantages of the acylation process of the invention are: - prior selective silylation of the p-hydroxy group in p-hydroxyphenylglycine is avoided, - the reaction is carried out in a concentrated solution of the reactants, so that with a given equipment gets a bigger yield in kg per day. charge, - the use of a p-hydroxyphenylglycyl chloride hydrochloride is avoided, which compound can only be prepared according to a process which is difficult to do and, moreover, is rather expensive in many countries due to their strict safety regulations, if the manufacturing authorization can be obtained at all 30 of the compound, - the use of large quantities of other auxiliary chemicals is avoided, - the desired final product can surprisingly be produced in economically advantageous initial yields of a quality acceptable under the existing health regulations, while reducing the number of cleaning steps with consequent minor losses of the desired compound, mixture of the preferred water-immiscible main solvent, e.g. dichloromethane, with a much smaller amount of a dipolar aprotic, water-miscible solvent enables a simple and economically advantageous recovery of the main solvent - the risk of unwanted and unexpected crystallization of 6-APA is practically not present, so that the process is reliable and pretty problem-free.
Det vil forstås, at mindst to uønskede sidereak-10 tioner vil blive taget i betragtning af fagfolk ved acy-lering ved hjælp af et blandet anhydrid. Disse sidereaktioner er: 1) acylering, ved hvilken der vil blive dannet alkoxycarbonylaminopenic illansyrederivater; 15 2) partiel racemisering af den N-beskyttede aminosyre, f.eks. under omdannelse af den N-beskyttede aminosyre eller et salt deraf til det blandede anhydrid.It will be appreciated that at least two undesirable side reactions will be considered by those skilled in the art of acylation by a mixed anhydride. These side reactions are: 1) acylation by which alkoxycarbonylaminopenic illanoic acid derivatives will be formed; 2) partial racemization of the N-protected amino acid, e.g. converting the N-protected amino acid or a salt thereof to the mixed anhydride.
Undgåelse af den første af disse sidereaktioner med forholdsvis simple foranstaltninger vil af fagfolk 20 blive betragtet som værende temmelig umuligt, da kobling af blandede anhydrider kan ske to steder i molekylet, og da blandede anhydrider naturligt er mere eller mindre labile og har tendens til at omdannes til to symmetriske anhydrider.Avoidance of the first of these side reactions by relatively simple measures will be considered by those skilled in the art to be quite impossible since coupling of mixed anhydrides can occur at two sites in the molecule and since mixed anhydrides are naturally more or less labile and tend to be converted for two symmetrical anhydrides.
25 Derfor vil fremstillingen af det blandede anhydrid såvel som omdannelsen af dette anhydrid med en aminosyre altid blive udført ved lave temperaturer.Therefore, the preparation of the mixed anhydride as well as the conversion of this anhydride with an amino acid will always be carried out at low temperatures.
Den anden uønskede sidereaktion (racemisering) kan navnlig undgås ved "trial and error methods" 30In particular, the second undesirable side reaction (racialization) can be avoided by "trial and error methods" 30
Selvom, ifølge litteraturen, ethylchlorformiat og - i tilfælde af racemisering ved anvendelse af denne reaktant, i noget mindre udstrækning - isobutylchlor-formiat, pivaloylchlorid og benzoylchlorid blev betragtet som egnede reaktanter, jvf. f.eks. de tyske patent-ansøgninger 2520647 og 2454841 og belgisk patent 824158, hvorimod anvendelse af methylchlorformiat absolut ikke skulle være foretrukket, har anvendelse af det billige methylchlorformiat overraskende vist sig at føre til 151024 13 væsentligt forbedrede resultater.Although, according to the literature, ethyl chloroformate and - in the case of racemization using this reactant, to a lesser extent - isobutyl chloroformate, pivaloyl chloride and benzoyl chloride were considered suitable reactants, cf. German patent applications 2520647 and 2454841 and Belgian patent 824158, while the use of methyl chloroformate should not be preferred, the use of the cheap methyl chloroformate has surprisingly been found to lead to significantly improved results.
Det bemærkes, at til fremstilling af det blandede anhydrid og den påfølgende acylering kommer der kun sådanne opløsningsmiddelsystemer i betragtning, som kan opfyl-5 de de krav, der stilles med hensyn til økonomi (genvindelighed, mulighed for tilbageførsel) og/eller økologi.It is noted that for the preparation of the mixed anhydride and the subsequent acylation, only such solvent systems are considered that can meet the requirements of economics (recyclability, recyclability) and / or ecology.
Disse krav er i overraskende grad opfyldt ved den absolut ikke forudsigelige anvendelse af de her foreslåede opløsningsmiddelsystemer.These requirements are surprisingly met by the absolutely unpredictable use of the solvent systems proposed here.
10 Anvendelse af de anførte opløsningsmjddelsystemer ved fremstilling af det blandede anhydrid har overraskende vist sig at medføre: a) en forbedret og endvidere mere reproducerbar og pålidelig dannelse af det blandede anhydrid, og så- 15 ledes et forbedret omdannelsesudbytte til den ønskede forbindelse/ b) et forbedret udnytte af den ønskede forbindelse i kombination med en samtidig forøgelse af koncentrationerne til et niveau, som er attraktivt efter de 20 nuværende økonomiske krav; c) den temmeligt uventede anvendelse af N,0-sily-leret 6-APA til reaktionen med de blandede anhydrider under opnåelse af de anførte udbytter; d) muligheden for at udføre såvel silylerings- 25 reaktionen som fremstillingen af det blandede anhydrid i et og samme med vand ublandbare hovedopløsningsmiddel, og merespecielt dichlormethan, hvilket medfører at den nødvendige genvinding af opløsningsmidler i høj grad forenkles .The use of the listed solvent systems in preparing the mixed anhydride has surprisingly been found to result in: a) an improved and, moreover, more reproducible and reliable formation of the mixed anhydride, and thus an improved conversion yield to the desired compound / b) improved utilization of the desired compound in combination with a simultaneous increase in concentrations to an attractive level according to the current 20 economic requirements; c) the rather unexpected use of N, 0-silylated 6-APA for the reaction with the mixed anhydrides to obtain the yields indicated; d) the ability to carry out both the silylation reaction and the preparation of the mixed anhydride in one main water-immiscible solvent, and more particularly dichloromethane, which greatly simplifies the necessary solvent recovery.
30 Ved udførelse af fremgangsmåden i teknisk måle stok vil anvendelse af meget effektivt tørrede opløsningsmidler og/eller Dane-salte med meget stor renhed være et ideal, der aldrig realiseres fuldstændigt; det foretrækkes at anvende et ringe overskud af de som udgangsmate- 35 rialer anvendte Dane-salte og af lavere alkylchlorformi-ater.In carrying out the process on a technical measuring stick, the use of very effectively dried solvents and / or Dane salts of very high purity will be an ideal that is never fully realized; it is preferred to use a slight excess of the Dane salts used as starting materials and of lower alkyl chloroforms.
151024 14141024 14
Ved en foretrukken udførelsesform for fremgangsmåden ifølge opfindelsen fremstilles amoxicillin-trihy-drat udfra tør methylenchlorid, 6-aminopenicillansyre og trimethylchlorsilan under tilstedeværelse af triethyl-5 amin i nøje afbalancerede indbyrdes mængder, og i en mængde på ca. to ækvivalenter med hensyn til 6-APA, af kalium-D-a- (l-carbomethoxypropen-2-yl) -amino-p'-hydroxy-phenylacetat, N-methylmorpholin som katalysator; et coopløsningsmiddel, udvalgt blandt N,N-dimethylacetå-10 mid, N-methylpyrrolidon, Ν,Ν-dimethylf ormamid og tetra-methylurinstof eller blandinger derafrog methylchlor-formiat,idet opløsningerne af den in situ fremstillede s i ly lerede 6-APA og det blandede anhydrid prékøles til -40°C, og reaktionen gennemføres på to timer ved en tem-15 peratur på -30°C, hvorpå amoxicillinen udvindes efter kendte metoder.In a preferred embodiment of the process according to the invention, amoxicillin trihydrate is prepared from dry methylene chloride, 6-aminopenicillanic acid and trimethylchlorosilane in the presence of triethylamine at carefully balanced proportions, and in an amount of approx. two equivalents of 6-APA, of potassium D-α- (1-carbomethoxypropen-2-yl) -amino-p'-hydroxy-phenyl acetate, N-methylmorpholine as catalyst; a co-solvent selected from N, N-dimethylacetamide, N-methylpyrrolidone, Ν, Ν-dimethylformamide and tetramethylurea or mixtures thereof of methyl chloroformate, the solutions of the in situ prepared 6-APA and the mixed anhydride is pre-cooled to -40 ° C and the reaction is carried out for two hours at a temperature of -30 ° C, after which the amoxicillin is recovered by known methods.
Et jamoxicillinpræparat fremstillet efter den beskrevne fremgangsmåde er særegent bl.a. ved følgende analysedata: 20A jamoxicillin preparation prepared according to the disclosed method is peculiar, inter alia. by the following analysis data: 20
Indhold bestemt ved hydroxylaminmetoden (beregnet på tørstofindhold) 99,8%Content determined by the hydroxylamine method (calculated on dry matter content) 99.8%
Indhold beregnet mercurometrisk (beregnet på tørstof) 98,7% 25 Flygtige komponenter 12,6% ved gas-chromatografi bestemte bestanddele: acetone 15 mg/kg methylen-chlorid 119,5 mg/kg methylisobutylketon 90 mg/kg 30 dimethylanilin 2 mg/kg [(ϊ]ϋ2ο (på tørstof) 301° pH-værdi 5,0 rumvægt, banket 6 gange: 216 ml/100g banket 50 gange: 204 ml/100 g 35 tungmetaller < 10 ppm sulfataske < o,l% kimtal < 10/g 151024 15 sønderdelingsprodukter: penicilloinsyre 0,4% penilloinsyre 0,6% opløselighed (klarhed) HCl: 0,6 EBC 55Content calculated mercurometric (based on dry matter) 98.7% 25 Volatile components 12.6% determined by gas chromatography: acetone 15 mg / kg methylene chloride 119.5 mg / kg methylisobutyl ketone 90 mg / kg 30 dimethylaniline 2 mg / kg [(ϊ] ϋ2ο (on dry matter) 301 ° pH 5.0 room weight, banked 6 times: 216 ml / 100g banked 50 times: 204 ml / 100 g 35 heavy metals <10 ppm sulfate ash <0, 1% seed count < 10 / g 151024 15 decomposition products: penicilloic acid 0.4% penilloic acid 0.6% solubility (clarity) HCl: 0.6 EBC 55
NH4OH 0,5 EBC XNH 4 OH 0.5 EBC X
5 XEBC = enhed for væskes klarhed (European Brewery5 XEBC = liquid clarity unit (European Brewery
Convention)Convention)
Fremgangsmåden ifølge opfindelsen illustreres ]_0 nærmere ved hjælp af nedenstående eksempler.The process of the invention is further illustrated by the following examples.
Eksempel IExample I
a) Fremstillingen af methoxycarbonyl-D-α-(1-car-bomethoxy-propen-2-yl)amino-p-hydroxyphenylacetat.a) The preparation of methoxycarbonyl-D-α- (1-carbomethoxy-propen-2-yl) amino-p-hydroxyphenyl acetate.
15 I en 2-liter reaktionsbeholder indføres 58 g kalium- D-a- (l-carbo-methoxypropen-2-yl)amino-p-hydroxyphe-nylacetat, og der tilsættes 200 ml methylenchlorid, som forud er tørret ved hjælp af en molekylesigte A4. Efter 20 at blandingen er afkølet til -40°C tilsættes under omrøring 25 ml tetramethylurinstof, hvilket bevirker, at temperaturen stiger til ca.-35°C.Derpå tilsættes 0,5 ml N-methylmorpholin og derefter 16 ml methylchloroformiat. Temperaturen hæves til ca. -30°C,og reaktionsblandingen 25 omrøres ved -30°C i to timer ved en pH-værdi på ca. 4. Reaktionsblandingen afkøles til -40°C.15 g of potassium Da- (1-carbo-methoxypropen-2-yl) amino-p-hydroxyphenyl acetate are added to a 2-liter reaction vessel and 200 ml of methylene chloride, which has been pre-dried by means of a molecular sieve . After the mixture has cooled to -40 ° C, 25 ml of tetramethylurea is added, with stirring, which causes the temperature to rise to about -35 ° C. Then 0.5 ml of N-methylmorpholine and then 16 ml of methyl chloroformate are added. The temperature is raised to approx. -30 ° C and the reaction mixture is stirred at -30 ° C for two hours at a pH of approx. 4. The reaction mixture is cooled to -40 ° C.
b) Silylering af 6-APA.b) Silylation of 6-APA.
30 I en én-liter reaktionsbeholder indføres 35 g 6- aminopenicillansyre og 350 ml methylenchlorid. Under omrøring tilsættes 45 ml triethylamin ved stuetemperatur og derpå 38 ml trimethylchlorosilan (TMCS) i løbet af ca. 10 min.,idet temperaturen holdes ved 20-25°C ved af-35 køling. Efter omrøring· i 1 time ved denne temperatur andrager pH-værdien ca. 7,5.30 g of 6-aminopenicillanic acid and 350 ml of methylene chloride are introduced into a one-liter reaction vessel. With stirring, 45 ml of triethylamine is added at room temperature and then 38 ml of trimethylchlorosilane (TMCS) over approx. 10 minutes, keeping the temperature at 20-25 ° C by cooling. After stirring for 1 hour at this temperature, the pH is approx. 7.5.
Ved tilsætning af 4 ml TMCS blev aflæsningen på skalaen af et Radiometer pH-meter af typen TTT2,C, for- 151024 16 bundet til en Radiometer GK 2401C elektrode, en pH-værdi på 6,0 + 0,2.By adding 4 ml of TMCS, the reading on the scale of a Radiometer pH meter of the type TTT2, C, was pre-linked to a Radiometer GK 2401C electrode, a pH of 6.0 + 0.2.
c) Fremstilling af 6- (D-cc-amino-p-hydroxyphenyl-5 acetamido)-penicillansyre.c) Preparation of 6- (D-cc-amino-p-hydroxyphenyl-acetamido) -penicillanic acid.
Reaktionsblandingen opnået i b) afkøles til -40° C og sættes på en gang til en opløsning af det blandede anhydrid, hvilket medfører, at temperaturen bliver -30°C.The reaction mixture obtained in b) is cooled to -40 ° C and added at once to a solution of the mixed anhydride, causing the temperature to become -30 ° C.
10 Reaktionsblandingen omrøres ved -30°C til -25°C i 1 time og sættes til 800 ml vand, således at temperaturen bliver 0°C og pH-værdien 2,5-3. pH-værdien af blandingen indstilles mellem 1,1 og 1,2 ved tilsætning af 18 ml koncentreret saltsyre (36 vægt-%, kemisk rent). Efter om-15 røring ved 0°C i 80 minutter er hydrolysen afsluttet.The reaction mixture is stirred at -30 ° C to -25 ° C for 1 hour and added to 800 ml of water so that the temperature becomes 0 ° C and the pH is 2.5-3. The pH of the mixture is adjusted between 1.1 and 1.2 by the addition of 18 ml of concentrated hydrochloric acid (36% by weight, chemically pure). After stirring at 0 ° C for 80 minutes, the hydrolysis is complete.
Lagene adskilles, og det vandige lag vaskes med 100 ml methylenchlorid. Det organiske lag vaskes med 50 ml destilleret vand,og efter ekstraktion af vaskevandet med det til vaskning anvendte methylenchlorid 20 blev vaskevandet sat til det vandige lag. Koblingsudbyttet er ca. 92%, bestemt på en prøve. Det vandige lag afkøles hurtigt til 0°C.The layers are separated and the aqueous layer is washed with 100 ml of methylene chloride. The organic layer is washed with 50 ml of distilled water and after extraction of the wash water with the methylene chloride 20 used for washing, the wash water is added to the aqueous layer. The coupling yield is approx. 92%, determined on a sample. The aqueous layer is rapidly cooled to 0 ° C.
Ved krystallisation fås den ønskede forbindelse, som efter filtrering vaskes med 100 ml 50% acetone-vand 25 og 100 ml acetone og tørres i vacuum ved ca. 30°C.Upon crystallization, the desired compound is obtained, which after filtration is washed with 100 ml of 50% acetone-water 25 and 100 ml of acetone and dried in vacuo at ca. 30 ° C.
Udbytte ca.55,5g amoxicillintrihydrat. Udbyttet andrager 82% af det teoretiske. Den tilbageværende moderlud indeholder yderligere ca. 10% amoxicillin.Yield about 5.5 g of amoxicillin trihydrate. The yield is 82% of the theoretical. The remaining mother liquor further contains approx. 10% amoxicillin.
3 0 Eksempel IIExample II
Under anvendelse af en lignende fremgangsmåde, som den i Eksempel I beskrevne, men med den afvigelse, at der anvendes 20 ml dimethylacetamid i stedet for 25 ml tetramethylurinstof, fås der også et koblingsudbytte, på 35 92% og 55,5 g rent amoxicillintrihydrat. Udbytte 82% af det teoretiske.Using a similar procedure to that described in Example I, but with the exception that 20 ml of dimethylacetamide is used instead of 25 ml of tetramethylurea, a coupling yield of 92% and 55.5 g of pure amoxicillin trihydrate is also obtained. Yield 82% of theory.
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Eksempel IIIExample III
a,l) Fremstillingen af ethoxycarbonyl D-a-(1-carbo-me thoxypropen-2-y1)-amino-p-hydroxyphenylaceta t.a, l) The preparation of ethoxycarbonyl D-α- (1-carboxymethoxypropen-2-yl) -amino-p-hydroxyphenylaceta t.
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En grundigt omrørt suspension af 12,97 g, 42,8 m-mol, kalium-D-a-(l-carbomethoxypropen-2-yl)-amino-p-hy-droxy-pheiylacetat i 98 ml methylisobutylketon (destilleret overi^CO^) og 33 ml tetrahydrofuran destilleret 10 over Redal afkøles til -10°C under en atmosfære af tør N2 Derpå tilsættes 0,05 ml (5 dråber fra en Pasteur-pipette) N-methylmorfelin, og derpå en opløsning af 4,2 ml, 44 m-mol, ethylchloroformiat, som forud er destilleret og udtaget under N2, i 15 ml methylisobutylketon. Reaktions-15 blandingen omrøres ved samme temperatur i 30 min. og suspensionen afkøles til -20°C.A thoroughly stirred suspension of 12.97 g, 42.8 m mole, potassium Da- (1-carbomethoxypropen-2-yl) -amino-p-hydroxy-pheylacetate in 98 ml of methyl isobutyl ketone (distilled over ) and 33 ml of tetrahydrofuran distilled over Redal are cooled to -10 ° C under an atmosphere of dry N2. Then 0.05 ml (5 drops of a Pasteur pipette) of N-methylmorphine is added and then a solution of 4.2 ml. 44 m mole, ethyl chloroformate, previously distilled and extracted under N 2, in 15 ml of methyl isobutyl ketone. The reaction mixture is stirred at the same temperature for 30 minutes. and the suspension is cooled to -20 ° C.
a, 2) Fremstillingen af methoxycarbonyl-D-α- (1-car-bomethoxypropen-2-yl)-amino-p-hydroxyphenylacetat.a, 2) The preparation of methoxycarbonyl-D-α- (1-carbomethoxypropen-2-yl) -amino-p-hydroxyphenyl acetate.
En ophyggeligt omrørt suspension af 45,6 mmol 20 kalium-D-a-(l-carbomethoxypropen-2-yl)-amino-p-hydroxyphenylacetat i 98 ml methylisobutylketon (destilleret over K2C02) og 33 ml tetrahydrofuran destilleret over Redal afkøles til -10°C under en atmosfære af tør N2·A carefully stirred suspension of 45.6 mmol of 20-potassium Da- (1-carbomethoxypropen-2-yl) -amino-p-hydroxyphenyl acetate in 98 ml of methyl isobutyl ketone (distilled over K 2 CO 2) and 33 ml of tetrahydrofuran distilled over Redal is cooled to -10 °. C under an atmosphere of dry N2 ·
Derpå tilsættes 0,05 ml N-methylmorpholin efterfulgt af 25 en opløsning af 46,8 mmol methylchlorformiat (renhed 97%) i 15 ml methylisobutylketon. Reaktionsblandingen omrøres ved samme temperatur i 30 minutter, og suspensionen afkøles til -20°C.Then 0.05 ml of N-methylmorpholine is added followed by a solution of 46.8 mmol of methyl chloroformate (97% purity) in 15 ml of methyl isobutyl ketone. The reaction mixture is stirred at the same temperature for 30 minutes and the suspension is cooled to -20 ° C.
30 b) Silylering af 6-APAB) Silylation of 6-APA
I en nitrogenatmosfære suspenderes 8,65 g, 40 mmol, 6-APA i 130 ml tør methylenchlorid og 11,2 ml, 80,6 mmol, triethyl-amin,og der tilsættes derpå 10,3 ml, 82 mmol, 35 trimethylchlorosilan. Denne blanding tilbagesvales under omrøring i 1 time og afkøles derpå i isbad til under 5°C. pH-Værdien måles med et Radiometer pH-meter TT2,C og en Radiometer GK 20401C elektrode og justeret til 6,4 ved 151024 18 afslutningen af silyleringsreaktionen.In a nitrogen atmosphere, 8.65 g, 40 mmol, 6-APA are suspended in 130 ml of dry methylene chloride and 11.2 ml, 80.6 mmol, triethylamine, and then 10.3 ml, 82 mmol, trimethyl chlorosilane is added. This mixture is refluxed with stirring for 1 hour and then cooled in an ice bath to below 5 ° C. The pH is measured with a Radiometer pH meter TT2, C and a Radiometer GK 20401C electrode and adjusted to 6.4 at the end of the silylation reaction.
c,l) Fremstilling af 6-(D-a-amino-p-hydroxyphenyl-acetamido)-penicillansyre.c, l) Preparation of 6- (D-α-amino-p-hydroxyphenyl-acetamido) -penicillanic acid.
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Under kraftig omrøring sættes den uklare opløsning af det under a) fremstillede Dane-anhydrid afkølet til -20°Cpå en gang til en afkølet opløsning af den sily lerede 6-APA fremstillet ifølge b), og blandingen om-10 røres i yderligere 20 min. på isbad. Derpå fjernes isbadet/ men omrøringen fortsættes under indførelse af nitrogen til stuetemperatur er nået (ca. 45 min.).With vigorous stirring, the turbid solution of the Dane anhydride prepared under a) is cooled to -20 ° C at once to a cooled solution of the silylated 6-APA prepared according to b) and the mixture is stirred for a further 20 minutes. . on the ice bath. The ice bath is then removed / but stirring is continued with introduction of nitrogen until room temperature is reached (about 45 minutes).
Blandingen udhældes under afkøling i 75 ml isafkølet vand, hvorefter pH-værdien, som har nået en værdi på 15 2,5-3, indstilles til 1-1,2 med koncentreret saltsyre, idet målingen sker med en Electrofact KCl-elektrode/ eller til 0,5-0,7 med en AgCl-elektrode.The mixture is poured off under cooling in 75 ml of ice-cooled water, after which the pH, which has reached a value of 2.5-3, is adjusted to 1-1.2 with concentrated hydrochloric acid, the measurement being done with an Electrofact KCl electrode / or to 0.5-0.7 with an AgCl electrode.
Der dannes intet bundfald ved 30 min,'s omrøring under køling med is, og der tilsættes, under køling med 20 is og omrøring, en opløsning af 10% KOH eller NaOH langsomt dråbevis, til pH-værdien forbliver konstant ved 5,2-5,3 (i ca. 1 time).No precipitate is formed at 30 minutes stirring with cooling with ice, and, while cooling with 20 ice and stirring, a solution of 10% KOH or NaOH is slowly added dropwise until the pH remains constant at 5.2 ° C. 5.3 (for about 1 hour).
Reaktionsblandingen henstilles i køleskab i 20 timer, og det dannede bundfald filtreres fra under anven-25 delse af et G3 glasfilter. Produktet vaskes omhyggeligt på filtret med vand, derpå med acetone.The reaction mixture is left in the refrigerator for 20 hours and the precipitate formed is filtered off using a G3 glass filter. The product is carefully washed on the filter with water, then with acetone.
Produktet tørres· i vacuum (frembragt med oliepumpe, ca. 1 mm Hg) over et tørremiddel i 16-24 timer. Der fås amoxicillintrihydrat i et udbytte på 71,2% med en renhed, 3 0 som målt mercurometrisk- åndrager 98,4% og målt biologisk 96,9%.The product is dried in a vacuum (produced with an oil pump, about 1 mm Hg) over a desiccant for 16-24 hours. Amoxicillin trihydrate is obtained in a yield of 71.2% with a purity, 30 as measured mercurometric breath 98.4% and measured biologically 96.9%.
c,2) Fremstilling af 6-(D-a-amino-p-hydroxyphe-nylacetamido)-penicillansyre.c, 2) Preparation of 6- (D-α-amino-p-hydroxyphenylacetamido) -penicillanic acid.
35 På i det væsentlige samme måde som beskrevet ovenfor under c,l) fremstilles amoxicillin-trihydrat i et udbytte på 83,5% med en renhed på 96%, målt ved hydroxylaminbestemmelse, en biologisk målt renhed på 151024 19 94,4% og en optisk drejning [a]2q på +294°, idet der gås ud fra den under a,2) fremstillede opløsning af Dane-anhydrid i stedet for den opløsning, der fremstilles under a,l).In substantially the same manner as described above under (c), amoxicillin trihydrate is prepared in a yield of 83.5% with a purity of 96% as measured by hydroxylamine determination, a biologically measured purity of 94.4% and an optical rotation [a] 2q of + 294 °, assuming the solution of Dane anhydride prepared under a, 2) instead of the solution prepared under a, l).
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Eksempel IVExample IV
På i det væsentlige samme mådesam beskrevet i eksempel III blev amoxicillintrihydrat opnået i et udbyt-10 te på 79,3% med en renhed på 97,6% bestemt ved hydroxy1-aminmåling, en biologisk renhedskvalitet på 95,4% og en optisk drejning [α3:°20 på + 300° ved at gå ud fra 45,6 mmol kalium-D-a-(l-carbomethoxypropen-2-yl)-amino-p-hy-droxyphenylacetat i 110 ml methylisobutylketon og 10 ml 15 N-methylpyrrolidon, 0,05 ml N-methylmorfolin, 46,8 mmol methylchloroformiat (renhed 97%) i 15 ml methylisobutylketon, 40 mmol 6-APA i 130 mml tør methylenchlorid, 80,6 mmol triethylamin og 82 mmol trimethylchlorosilan.In substantially the same manner described in Example III, amoxicillin trihydrate was obtained in a yield of 79.3% with a purity of 97.6% as determined by hydroxy1 amine measurement, a biological purity grade of 95.4% and an optical rotation. [α3: +20 at + 300 °, starting from 45.6 mmol of potassium Da- (1-carbomethoxypropen-2-yl) -amino-p-hydroxyphenyl acetate in 110 ml of methyl isobutyl ketone and 10 ml of 15 N-methylpyrrolidone , 0.05 ml of N-methylmorpholine, 46.8 mmol of methyl chloroformate (97% purity) in 15 ml of methyl isobutyl ketone, 40 mmol of 6-APA in 130 mml of dry methylene chloride, 80.6 mmol of triethylamine and 82 mmol of trimethylchlorosilane.
pH-værdien målt med et Radiometer pH-meter type 20 TTT2,C og en Radiometer SK 2401C elektrode blev indstillet til 6,7 ved.afslutningen af silyleringsreaktionen.The pH value measured with a Radiometer pH meter type 20 TTT2, C and a Radiometer SK 2401C electrode was set to 6.7 at the end of the silylation reaction.
Eksempel VExample V
25 a) Fremstilling af methoxycarbonyl D-α-(1-carbo- methoxypropen-2-yl)-amino-p-hydroxyphenylacetat.A) Preparation of methoxycarbonyl D-α- (1-carbomethoxypropen-2-yl) -amino-p-hydroxyphenyl acetate.
I en 2-li'ter reaktionsbeholder indføres 58..g kalium-D-a- (l-carbomethoxy-propen-2-yl)-amino-p-hydroxyphenylacetat og 400 ml tøt methylisobutylketon. Efter 30 afkøling til -15°C tilsættes under omrøring 0,5 ml N-methylmorfolin og 16 ml methylchloroformiat. Reaktionsblandingen omrøres ved -11°C i 1,5 timer og afkøles derpå til -43°C.Into a 2-liter reaction vessel is introduced 58 µg of potassium D-α- (1-carbomethoxy-propen-2-yl) -amino-p-hydroxyphenyl acetate and 400 ml of dry methyl isobutyl ketone. After cooling to -15 ° C, 0.5 ml of N-methylmorpholine and 16 ml of methyl chloroformate are added with stirring. The reaction mixture is stirred at -11 ° C for 1.5 hours and then cooled to -43 ° C.
151024 20 b) Silylering af 6-APA.B) Silylation of 6-APA.
I en 1-liter reaktionsbeholder indføres 35 g 6-aminopenicillansyre og 400 ml methylenchlorid. Efter tilsætning af 73 g bis(trimethylsilyl)urinstof tilbagesva-5 les blandingen i ca 2,5 timer. Blandingen afkøles til 20°C. "pH-værdien" på skalaen af et Radiometer pH-meter type TTT2,C forbundet med en Radiometer GK-2401C elektrode, aflæses til 6,3.Into a 1-liter reaction vessel is introduced 35 g of 6-aminopenicillanic acid and 400 ml of methylene chloride. After adding 73 g of bis (trimethylsilyl) urea, the mixture is refluxed for about 2.5 hours. The mixture is cooled to 20 ° C. The "pH value" on the scale of a Radiometer pH meter type TTT2, C connected to a Radiometer GK-2401C electrode, is read to 6.3.
10 c) Efter afkøling sættes den under b) opnåede blanding så hurtigt som muligt til den afkølede opløsning af det blandede anhydrid, således at der nås en temperatur på -30°C. Reaktionsblandingen omrøres ved -30°C til -25°C i 1 time og sættes til 800 ml vand, så- 15 ledes at temperaturen bliver 0°C og pH-værdien 2,5-3. Udvindingen sker på lignende måde som beskrevet i eksempel I.C) After cooling, the mixture obtained under b) is added as quickly as possible to the cooled solution of the mixed anhydride so that a temperature of -30 ° C is reached. The reaction mixture is stirred at -30 ° C to -25 ° C for 1 hour and added to 800 ml of water, so that the temperature becomes 0 ° C and the pH is 2.5-3. The extraction is done in a similar manner as described in Example I.
Udbytte 48,4% amoxicillintrihydrat med en biologisk målt renhedskvalitet på 96,8%. Udbytte 71,3% af det 20 teoretiske. Den tilbageværende moder-lud indeholder y-derligere ca. 10% amoxicillin.Yield 48.4% amoxicillin trihydrate with a biologically measured purity of 96.8%. Yield 71.3% of the 20 theoretical. The remaining mother liquor contains γ-further approx. 10% amoxicillin.
Eksempel viExample vi
25 På lignende måde som beskrevet i eksempel VIn a similar manner as described in Example V
fås-48,3 g amoxicillintrihydrat med en renhed på 97,7% ved omsætning af methoxycarbonyl-D-α- (1-carbo-methoxy-propen-2-yl)-amino-p-hydroxyphenylacetat og 35 g 6-amino-penicillansyre, som forud er silyleret med 72,5 g bis- O Λ (trimethylsilyl)acetamid i stedet for med bis(trimethylsilyl) urinstof.48.3 g of amoxicillin trihydrate with a purity of 97.7% are obtained by reaction of methoxycarbonyl-D-α- (1-carbo-methoxy-propen-2-yl) -amino-p-hydroxyphenyl acetate and 35 g of 6-amino penicillanic acid, previously silylated with 72.5 g of bis-O-(trimethylsilyl) acetamide instead of with bis (trimethylsilyl) urea.
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Eksempel VIIExample VII
a) Fremstilling af methoxycarbonyl-D-α-(1-carbo-methoxypropen-2-yl)-amino-p-hydroxyphenylacetat.a) Preparation of methoxycarbonyl-D-α- (1-carbo-methoxypropen-2-yl) -amino-p-hydroxyphenyl acetate.
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En omhyggeligt omrørt suspension af 58 g kalium-D-a-(l-carbomethoxypropen-2-yl)amino-p-hydroxyphenylace-tat i 400 ml tør methylisobutylketon (destilleret over K2C03^ afkøles til -17°C under en atmosfære af tør nitro-10 gen. Derpå tilsættes 0,5 ml N-methylmorpholin efterfulgt af 16 ml methylchloroformiat. Temperaturen stiger til -12°C,og reaktionsblandingen omrøres ved denne temperatur i 1,5 time. "pH-værdien" på skalaen af et Radiometer pH-meter type TTT2,C forbundet med en Radiometer GK-2401 15 C elektrode,viser en slutværdi på 3,7. Reaktionsblandingen afkøles til -40°C.A carefully stirred suspension of 58 g of potassium Da- (1-carbomethoxypropen-2-yl) amino-p-hydroxyphenyl acetate in 400 ml of dry methyl isobutyl ketone (distilled over K 2 CO 3 3) is cooled to -17 ° C under an atmosphere of dry nitrogen. Then add 0.5 ml of N-methylmorpholine followed by 16 ml of methyl chloroformate, the temperature rises to -12 ° C and the reaction mixture is stirred at this temperature for 1.5 hours. meter type TTT2, C connected to a Radiometer GK-2401 15 C electrode, shows a final value of 3.7 The reaction mixture is cooled to -40 ° C.
b) Silylering af 6-APAb) Silylation of 6-APA
20 35 g 6-APA sættes til 400 ml methylenchlorid.35 g of 6-APA are added to 400 ml of methylene chloride.
Efter tilsætning af 43 ml triethylamin ved stuetemperatur og under omrøring tilføjes 35 ml trimethylchlorosilan i løbet af ca. 10 min. ved en temperatur på 20-25°C.After the addition of 43 ml of triethylamine at room temperature and with stirring, 35 ml of trimethyl chlorosilane is added over approx. 10 min. at a temperature of 20-25 ° C.
Efter yderligere omrøring i 1 time indstilles "pH-værdi-25 en" til en sluttelig værdi på 6,7 ved tilsætning af 4*9 ml trimethylchlorosilan. Blandingen afkøles til -40°C.After further stirring for 1 hour, the "pH 25" is adjusted to a final value of 6.7 by the addition of 4 * 9 ml of trimethyl chlorosilane. The mixture is cooled to -40 ° C.
c) Den under b) opnåede afkølede opløsning sættes så hurtigt som muligt til den afkølede opløsning af det 30 blandede anhydrid, fremstillet under a), hvorved temperaturen stiger til -30°C. Reaktionsblandingen omrøres ved -30°C i en time og sættes derpå til 800 ml vand og 15 ml koncentreret (36%) HCl-opløsning, hvis temperatur er lo° C. Efter yderligere omrøring ved 0°C adskilles lagene, og 35 det vandige lag vaskes medlOO ml methylenchlorid. Det organiske lag vaskes med 50 ml destilleret vand, og efter ekstraktion af vaskevandet med det som vaskemedium anvendte methylenchlorid sammenblandes de vandige lag.c) The cooled solution obtained under b) is added as quickly as possible to the cooled solution of the 30 mixed anhydride prepared under a), whereby the temperature rises to -30 ° C. The reaction mixture is stirred at -30 ° C for one hour and then added to 800 ml of water and 15 ml of concentrated (36%) HCl solution, the temperature of which is 100 ° C. After further stirring at 0 ° C, the layers are separated and the aqueous layers are washed with 100 ml of methylene chloride. The organic layer is washed with 50 ml of distilled water and after extraction of the wash water with the methylene chloride used as the washing medium, the aqueous layers are mixed.
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Acyleringsudbyttet synes at være ca. 89% bestemt ved et mikrobiologisk forsøg på en prøve. Det vandige lag afkøles hurtigt til 0°Ο, og der nås en sluttelig pH-værdi på 5,2. Den krystalliserede ønskede forbindelse vaskes 5 med 100 ml af ernacetone-vand (1/1) blanding og med 100 ml acetone, og tørres under vacuum ved ca. 30°C.The acylation yield appears to be approx. 89% determined by a microbiological test on a sample. The aqueous layer is rapidly cooled to 0 ° Ο and a final pH of 5.2 is reached. The crystallized desired compound is washed 5 with 100 ml of ernacetone-water (1/1) mixture and with 100 ml of acetone, and dried under vacuum at ca. 30 ° C.
Udbyttet er 54,0 g amoxicillintrihydrat med en mercurometrisk bestemt renhed på 98,7% og en renhed på 99,8% bestemt efter hydroxylaminmetoden, og med en optisk 10 drejning tøl^o på +300° baseret på tørstof. Udbyttet er 80% af det teoretiske.The yield is 54.0 g of amoxicillin trihydrate with a mercurometric determined purity of 98.7% and a purity of 99.8% determined by the hydroxylamine method and with an optical rotation of + 300 ° based on dry matter. The yield is 80% of the theoretical.
Den tilbageværende moder-lud indeholder en yderligere amoxicillinmængde på 6-7%.The remaining mother liquor contains an additional amoxicillin amount of 6-7%.
15 Eksempel VIIIExample VIII
På lignende måde som beskrevet i eksempel V-VII fås 55,3 g amoxicillintrihydrat i et udbytte på 81,5% med en renhed på 99,8% bestemt efter en metode baseret 20 på hydroxylaminmåling, en biologisk renhedskvalitet på 95%, en mercurometrisk målt^renhed på 98,6%, og en optisk drejning P® +300°, udfra 58 g kalium-D-a-(1-car- bomethoxypropen-2-yl)-amino-p-hydroxyphenylacetat i 200 ml methylenchlorid og 20 ml N-methylpyrrolindon, 0,5 25 ml N-methylmorpholin, 16 ml methylchloroformiat, 35 g 6-ΑΡΔ i 200 ml methylenchlorid, 43 ml triethylamin og 35 ml trimethylchlorosilan. "pH” målt med et Radiometer pH-meter TTT2,C og en Radiometer GK 2401C elektrode blev indstillet til 6,7 ved afslutningen af silyleringsreak-30 tionen, og opløsningen af det blandede anhydrid såvel som opløsningen af silyleret 6-APA var forudafkølet ned til -40°C og blev omsat ved -30°C i 2 timer (analyseret acyleringsudbytte 93,1%) 35 Eksempel ix På lignende måde som beskrevet i eksemplerne V-VII fremstilles '56,1 g amoxicillintrihydrat i et udbytte på 151024 23 82,7% med en renhed på 99,7% bestemt efter hydroxylamin-metoden, en biologisk renhedskvalitet på 95%, en mercu-rometrisk bestemt renhed på 98,7% og en optisk drejning [a]°2o På +300°, udfra 58 g kalium-D-a-(1-carbomethoxy-5 prqpen-2-yl). -amino-p-hydroxyphenylacetat i 200 ml methy-lenchlorid og 20 ml Ν,Ν-dimethylacetamid, og 0,5 ml lime thylmorpholin, 16 ml methylchloroformiat, 35 g 6-APA i 200 ml methylenchlorid, 43 ml triethylamin og 35 ml trimethylchlorosilan. "pH" målt med et Radiometer pH-10 meter TTT2,C og en Radiometer GK 2401 C elektrode blev indstillet til 6,7 ved afslutningen af silyleringsreaktionen, og opløsningerne af det blandede anhydrid og af silyleret 6-APA blev forkølet til -40°C og omsat ved -30°C i to timer (analyseret acyleringsudbytte 95%).In a similar manner as described in Examples V-VII, 55.3 g of amoxicillin trihydrate is obtained in a yield of 81.5% with a purity of 99.8% determined by a method based on hydroxylamine measurement, a biological purity grade of 95%, a mercurometric measured purity of 98.6% and an optical rotation P® + 300 °, from 58 g of potassium Da- (1-carbomethoxypropen-2-yl) -amino-p-hydroxyphenyl acetate in 200 ml of methylene chloride and 20 ml N-methylpyrrolindone, 0.5 25 ml N-methylmorpholine, 16 ml methyl chloroformate, 35 g 6-ΑΡΔ in 200 ml methylene chloride, 43 ml triethylamine and 35 ml trimethyl chlorosilane. "pH" measured with a Radiometer pH meter TTT2, C and a Radiometer GK 2401C electrode was set to 6.7 at the end of the silylation reaction and the solution of the mixed anhydride as well as the solution of silylated 6-APA was precooled to -40 ° C and reacted at -30 ° C for 2 hours (analyzed acylation yield 93.1%) Example ix In a similar manner as described in Examples V-VII, 56.1 g of amoxicillin trihydrate is prepared in a yield of 15 82.7% with a purity of 99.7% determined by the hydroxylamine method, a biological purity grade of 95%, a mercometrically determined purity of 98.7% and an optical rotation [a] ° 20 ° + 300 °, from 58 g of potassium Da- (1-carbomethoxy-5-propen-2-yl) -amino-p-hydroxyphenyl acetate in 200 ml of methylene chloride and 20 ml of Ν, Ν-dimethylacetamide, and 0.5 ml of lime thylmorpholine, 16 ml of methyl chloroformate, 35 g of 6-APA in 200 ml of methylene chloride, 43 ml of triethylamine and 35 ml of trimethyl chlorosilane. "pH" measured with a Radiometer pH-10 meter TTT2, C and a Radiometer G The K 2401 C electrode was adjusted to 6.7 at the end of the silylation reaction and the solutions of the mixed anhydride and of the silylated 6-APA were cooled to -40 ° C and reacted at -30 ° C for two hours (assayed acylation yield 95%). .
1515
Eksempel XExample X
På lignende måde som beskrevet i eksemplerne V-VII blev amoxicillin fremstillet i et 80% acylerings-20 udbytte udfra 58,0 g kalium-D-α-(1-carbomethoxypropen-2-yl)-amino-p-hydroxyphenylacetat i 400 ml methylenchlorid, 20 mlN,N-dimethylformamid, 0,5 ml N-methylmorpholin, 16 ml methylchloroformiat, 35 g 6-APA i 200 ml methylen-chlorid, 43 ml triethylamin og 35 ml trimethylchlorosil-25 an. "pH" målt med samme udstyr som i de foregående eksempler blev indstillet til 6,7 ved afslutningen af silyleringsreaktionen, og opløsningerne af det blandede anhydrid og af silyleret 6-APA blev forkølet til -40°C og omsat ved -30°C i to timer.In a similar manner to those described in Examples V-VII, amoxicillin was prepared in an 80% acylation yield from 58.0 g of potassium D-α- (1-carbomethoxypropen-2-yl) amino p-hydroxyphenyl acetate in 400 ml. methylene chloride, 20 ml of N, N-dimethylformamide, 0.5 ml of N-methylmorpholine, 16 ml of methyl chloroformate, 35 g of 6-APA in 200 ml of methylene chloride, 43 ml of triethylamine and 35 ml of trimethylchlorosilane. The "pH" measured with the same equipment as in the previous examples was adjusted to 6.7 at the end of the silylation reaction and the solutions of the mixed anhydride and of the silylated 6-APA were cooled to -40 ° C and reacted at -30 ° C. two hours.
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK459383A DK152503C (en) | 1977-09-06 | 1983-10-05 | METHOD FOR PREPARING CEPHALOSPORANIC ACID DERIVATIVES CONTAINING A D-ALFA AMINO (P-HYDROXYPHENYL) ACETAMIDOGRUPE |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL7709812 | 1977-09-06 | ||
| NL7709812.A NL162387C (en) | 1977-09-06 | 1977-09-06 | PROCESS FOR PREPARING 6- (D-ALPHA-AMINO-P- HYDROXYPHENYLACETAMIDO) PENICILLANIC ACID. |
| EP78200140A EP0001133B1 (en) | 1977-09-06 | 1978-08-11 | Process for the preparation of 6- d-alpha-amino-(p-hydroxyphenyl)-acetamido penicillanic acid |
| EP78200140 | 1978-08-11 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK391478A DK391478A (en) | 1979-03-07 |
| DK151024B true DK151024B (en) | 1987-10-12 |
| DK151024C DK151024C (en) | 1988-02-29 |
Family
ID=19829143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK391478A DK151024C (en) | 1977-09-06 | 1978-09-05 | METHOD FOR PREPARING 6- (D-ALFA-AMINO- (P-HYDROXYPHENYL) ACETAMIDO) -PENICILLANIC ACID |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US4128547A (en) |
| EP (2) | EP0001133B1 (en) |
| JP (1) | JPS5495590A (en) |
| CA (1) | CA1111413A (en) |
| DE (2) | DE2861547D1 (en) |
| DK (1) | DK151024C (en) |
| FI (1) | FI70714C (en) |
| IE (1) | IE48466B1 (en) |
| IT (1) | IT1160632B (en) |
| NL (1) | NL162387C (en) |
| NO (2) | NO160209C (en) |
| PT (1) | PT68511A (en) |
Families Citing this family (28)
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|---|---|---|---|---|
| GB1532682A (en) * | 1976-04-27 | 1978-11-22 | Bristol Myers Co | Process for the preparation of cephadroxil |
| ES459494A1 (en) * | 1977-06-04 | 1978-05-01 | Palomo Coll A Luis | Process for the preparation of hydroxy-alpha-amino-benzyl penicillin |
| US4278600A (en) * | 1979-03-19 | 1981-07-14 | Bristol-Myers Company | Production of penicillins |
| US4240960A (en) * | 1979-03-19 | 1980-12-23 | Bristol-Myers Company | Trimethylsilyl substituted penicillins |
| US4310458A (en) * | 1979-03-19 | 1982-01-12 | Bristol-Myers Company | Production of penicillins |
| US4231954A (en) * | 1979-04-20 | 1980-11-04 | American Home Products Corporation | Dane salt and process for preparing aminopenicillins therefrom |
| US4301072A (en) * | 1979-04-20 | 1981-11-17 | American Home Products Corporation | Process for preparing aminopenicillins |
| FR2457295A1 (en) * | 1979-05-25 | 1980-12-19 | Glaxo Group Ltd | INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF CEPHALOSPORINS |
| US4351766A (en) * | 1979-07-12 | 1982-09-28 | Bristol-Myers Company | Production of penicillins |
| IT1126544B (en) * | 1979-12-07 | 1986-05-21 | Dobfar Spa | PROCEDURE FOR THE PREPARATION OF 7-AMINO-DESACETOXY CEPHALOSPORANIC ACID DERIVATIVES |
| NL7908867A (en) * | 1979-12-10 | 1981-07-01 | Gist Brocades Nv | PROCESS FOR PREPARING 6-AMINOPENICILLANIC ACID -1-1-DIOXIDE AND ITS SALTS. |
| US4366098A (en) * | 1980-11-26 | 1982-12-28 | American Home Products Corporation | Process for preparing aminopenicillins |
| GB2240102B (en) * | 1990-01-22 | 1993-10-20 | Biochemie Gmbh | Improvements in or relating to beta lactam production |
| AT396238B (en) * | 1991-05-17 | 1993-07-26 | Biochemie Gmbh | Novel process and intermediates for the preparation of 3- vinylcephalosporin compounds |
| AT395854B (en) * | 1991-05-24 | 1993-03-25 | Biochemie Gmbh | NEW METHOD FOR PRODUCING 7-AMINO-3AZIDOMETHYL-3-CEPHEM-4-CARBONIC ACID AND THEIR DERIVATIVES |
| GB9115203D0 (en) * | 1991-07-15 | 1991-08-28 | Biochemie Gmbh | Improvements in or relating to beta lactam production |
| AT396108B (en) * | 1991-08-21 | 1993-06-25 | Biochemie Gmbh | NEW PROCESS AND NEW INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF 7-AMINOCEPHALOSPORANIC ACID DERIVATIVES |
| ES2050621B1 (en) * | 1992-11-06 | 1994-12-16 | Antibioticos Sa | AN IMPROVED PROCEDURE FOR THE PREPARATION OF 6 - * - AMINOPENICILLINS. |
| GB9423459D0 (en) * | 1994-11-21 | 1995-01-11 | Biochemie Gmbh | Silylation process |
| KR100389644B1 (en) * | 2001-02-26 | 2003-06-27 | 한미약품 주식회사 | 4-hydroxyphenylglycine anhydrides and process for the preparation thereof |
| US20040077849A1 (en) * | 2002-10-16 | 2004-04-22 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of cefadroxil |
| US7230097B2 (en) * | 2003-03-10 | 2007-06-12 | Lupin Ltd. | Process for preparation of 7-[α-Amino (4-hydroxyphenyl) acetamido]-3-substituted-3-cephem-4-carboxylic acid |
| CN101772505B (en) * | 2007-07-30 | 2013-07-10 | 中化帝斯曼制药有限公司荷兰公司 | Compositions comprising beta lactam compounds |
| ES2359600T3 (en) * | 2007-07-30 | 2011-05-25 | Dsm Ip Assets B.V. | PROCESS FOR SILILAR BETA-LACTAMAS. |
| CN103108879B (en) * | 2010-09-07 | 2016-08-17 | 中化帝斯曼制药有限公司荷兰公司 | For the method producing cephalosporins |
| CN103360412B (en) * | 2013-06-08 | 2015-08-19 | 苏州中联化学制药有限公司 | A kind of synthetic method of S 578 |
| CN103772414B (en) * | 2013-12-31 | 2016-03-09 | 福建省福抗药业股份有限公司 | A kind of preparation method preparing cefatrizine propylene glycol |
| CN107986991A (en) * | 2017-12-18 | 2018-05-04 | 湖南国发精细化工科技有限公司 | The synthetic method of N- chloroformyls-N [(4- trifluoromethoxies) phenyl] methyl carbamate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1073530A (en) * | 1962-12-14 | 1967-06-28 | Astra Apotekarnes Kem Fab | Process for the preparation of cephalosporins |
| GB1339605A (en) * | 1972-03-28 | 1973-12-05 | Beecham Group Ltd | Penicillin synthesis |
| US3946003A (en) * | 1974-08-20 | 1976-03-23 | Eli Lilly And Company | Hydroxy substituted phenylglycylamido-3-heterocyclic thiomethyl cephalosporins |
| GB1460914A (en) * | 1972-12-26 | 1977-01-06 | Bristol Myers Co | 3-thiolated-7-acylamido-cephalosporanic acid derivatives processes for preparing them and pharmaceutical compositions 0mprising them |
| DK142913B (en) * | 1972-06-14 | 1981-02-23 | Smith Kline French Lab | Analogous Process for Preparation of Cephalosporanoic Acid Derivatives. |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5318515B2 (en) * | 1971-12-17 | 1978-06-15 | ||
| US3965098A (en) * | 1972-11-29 | 1976-06-22 | American Home Products Corporation | Intermediates for preparing cephalosporins and methods of production |
| PL87745B1 (en) * | 1973-04-18 | 1976-07-31 | Politechnika Gdanska Danzig (Polen) | |
| YU36733B (en) * | 1973-10-26 | 1984-08-31 | Krka Novo Mesto | Process for preparing pure anhydrous 6-zd-(-)-alfa-aminophenylacetamidoc-penicillanic acid |
| US3912719A (en) * | 1974-01-28 | 1975-10-14 | Bristol Myers Co | Production of semisynthetic penicillins |
| NL7414083A (en) * | 1974-05-17 | 1975-11-19 | Archifar Ind Chim Trentino | PROCESS FOR THE PREPARATION OF HYDROXYL-CONTAINING ANTIBIOTICS. |
| US4148817A (en) * | 1976-03-25 | 1979-04-10 | Eli Lilly And Company | Process and intermediates for preparing cephalosporin antibiotics |
-
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- 1977-09-06 NL NL7709812.A patent/NL162387C/en not_active IP Right Cessation
- 1977-11-25 US US05/854,821 patent/US4128547A/en not_active Expired - Lifetime
-
1978
- 1978-08-11 EP EP78200140A patent/EP0001133B1/en not_active Expired
- 1978-08-11 DE DE7878200140T patent/DE2861547D1/en not_active Expired
- 1978-08-11 EP EP80200702A patent/EP0019345B1/en not_active Expired
- 1978-08-11 DE DE8080200702T patent/DE2862468D1/en not_active Expired
- 1978-09-05 DK DK391478A patent/DK151024C/en not_active IP Right Cessation
- 1978-09-05 IT IT69044/78A patent/IT1160632B/en active
- 1978-09-05 JP JP10903078A patent/JPS5495590A/en active Granted
- 1978-09-05 FI FI782719A patent/FI70714C/en not_active IP Right Cessation
- 1978-09-05 CA CA310,665A patent/CA1111413A/en not_active Expired
- 1978-09-05 NO NO783025A patent/NO160209C/en unknown
- 1978-09-05 PT PT68511A patent/PT68511A/en unknown
- 1978-09-06 IE IE1802/78A patent/IE48466B1/en not_active IP Right Cessation
-
1980
- 1980-10-03 US US06/193,801 patent/US4358588A/en not_active Expired - Lifetime
-
1985
- 1985-10-24 NO NO85854260A patent/NO161495C/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1073530A (en) * | 1962-12-14 | 1967-06-28 | Astra Apotekarnes Kem Fab | Process for the preparation of cephalosporins |
| GB1339605A (en) * | 1972-03-28 | 1973-12-05 | Beecham Group Ltd | Penicillin synthesis |
| DK142913B (en) * | 1972-06-14 | 1981-02-23 | Smith Kline French Lab | Analogous Process for Preparation of Cephalosporanoic Acid Derivatives. |
| GB1460914A (en) * | 1972-12-26 | 1977-01-06 | Bristol Myers Co | 3-thiolated-7-acylamido-cephalosporanic acid derivatives processes for preparing them and pharmaceutical compositions 0mprising them |
| US3946003A (en) * | 1974-08-20 | 1976-03-23 | Eli Lilly And Company | Hydroxy substituted phenylglycylamido-3-heterocyclic thiomethyl cephalosporins |
Also Published As
| Publication number | Publication date |
|---|---|
| IE48466B1 (en) | 1985-02-06 |
| NL162387B (en) | 1979-12-17 |
| NO161495C (en) | 1989-08-23 |
| PT68511A (en) | 1978-10-01 |
| IT7869044A0 (en) | 1978-09-05 |
| FI782719A (en) | 1979-03-07 |
| FI70714C (en) | 1986-10-06 |
| NO783025L (en) | 1979-03-07 |
| NO161495B (en) | 1989-05-16 |
| JPS6354717B2 (en) | 1988-10-28 |
| NO160209C (en) | 1989-03-22 |
| DE2862468D1 (en) | 1985-07-25 |
| NL162387C (en) | 1980-05-16 |
| US4128547A (en) | 1978-12-05 |
| CA1111413A (en) | 1981-10-27 |
| JPS5495590A (en) | 1979-07-28 |
| EP0019345A1 (en) | 1980-11-26 |
| NO854260L (en) | 1979-03-07 |
| FI70714B (en) | 1986-06-26 |
| US4358588A (en) | 1982-11-09 |
| DK151024C (en) | 1988-02-29 |
| IT1160632B (en) | 1987-03-11 |
| EP0019345B1 (en) | 1985-06-19 |
| NO160209B (en) | 1988-12-12 |
| DE2861547D1 (en) | 1982-03-04 |
| EP0001133B1 (en) | 1982-01-20 |
| DK391478A (en) | 1979-03-07 |
| EP0001133A1 (en) | 1979-03-21 |
| IE781802L (en) | 1979-03-06 |
| NL7709812A (en) | 1979-03-08 |
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